diff --git a/crates/uv-python/src/environment.rs b/crates/uv-python/src/environment.rs
index 04cae0df9..311f0ee1a 100644
--- a/crates/uv-python/src/environment.rs
+++ b/crates/uv-python/src/environment.rs
@@ -270,6 +270,16 @@ impl PythonEnvironment {
         Ok(PyVenvConfiguration::parse(self.0.root.join("pyvenv.cfg"))?)
     }
 
+    /// Set a key-value pair in the `pyvenv.cfg` file.
+    pub fn set_pyvenv_cfg(&self, key: &str, value: &str) -> Result<(), Error> {
+        let content = fs_err::read_to_string(self.0.root.join("pyvenv.cfg"))?;
+        fs_err::write(
+            self.0.root.join("pyvenv.cfg"),
+            PyVenvConfiguration::set(&content, key, value),
+        )?;
+        Ok(())
+    }
+
     /// Returns `true` if the environment is "relocatable".
     pub fn relocatable(&self) -> bool {
         self.cfg().is_ok_and(|cfg| cfg.is_relocatable())
diff --git a/crates/uv-python/src/virtualenv.rs b/crates/uv-python/src/virtualenv.rs
index 2463d1a87..75e4e10d8 100644
--- a/crates/uv-python/src/virtualenv.rs
+++ b/crates/uv-python/src/virtualenv.rs
@@ -1,3 +1,4 @@
+use std::borrow::Cow;
 use std::{
     env, io,
     path::{Path, PathBuf},
@@ -5,6 +6,7 @@ use std::{
 
 use fs_err as fs;
 use thiserror::Error;
+
 use uv_pypi_types::Scheme;
 use uv_static::EnvVars;
 
@@ -37,6 +39,8 @@ pub struct PyVenvConfiguration {
     pub(crate) relocatable: bool,
     /// Was the virtual environment populated with seed packages?
     pub(crate) seed: bool,
+    /// Should the virtual environment include system site packages?
+    pub(crate) include_system_side_packages: bool,
 }
 
 #[derive(Debug, Error)]
@@ -188,6 +192,7 @@ impl PyVenvConfiguration {
         let mut uv = false;
         let mut relocatable = false;
         let mut seed = false;
+        let mut include_system_side_packages = false;
 
         // Per https://snarky.ca/how-virtual-environments-work/, the `pyvenv.cfg` file is not a
         // valid INI file, and is instead expected to be parsed by partitioning each line on the
@@ -211,6 +216,9 @@ impl PyVenvConfiguration {
                 "seed" => {
                     seed = value.trim().to_lowercase() == "true";
                 }
+                "include-system-site-packages" => {
+                    include_system_side_packages = value.trim().to_lowercase() == "true";
+                }
                 _ => {}
             }
         }
@@ -220,6 +228,7 @@ impl PyVenvConfiguration {
             uv,
             relocatable,
             seed,
+            include_system_side_packages,
         })
     }
 
@@ -242,4 +251,119 @@ impl PyVenvConfiguration {
     pub fn is_seed(&self) -> bool {
         self.seed
     }
+
+    /// Returns true if the virtual environment should include system site packages.
+    pub fn include_system_side_packages(&self) -> bool {
+        self.include_system_side_packages
+    }
+
+    /// Set the key-value pair in the `pyvenv.cfg` file.
+    pub fn set(content: &str, key: &str, value: &str) -> String {
+        let mut lines = content.lines().map(Cow::Borrowed).collect::<Vec<_>>();
+        let mut found = false;
+        for line in &mut lines {
+            if let Some((lhs, _)) = line.split_once('=') {
+                if lhs.trim() == key {
+                    *line = Cow::Owned(format!("{key} = {value}"));
+                    found = true;
+                    break;
+                }
+            }
+        }
+        if !found {
+            lines.push(Cow::Owned(format!("{key} = {value}")));
+        }
+        if lines.is_empty() {
+            String::new()
+        } else {
+            format!("{}\n", lines.join("\n"))
+        }
+    }
+}
+
+#[cfg(test)]
+mod tests {
+    use indoc::indoc;
+
+    use super::*;
+
+    #[test]
+    fn test_set_existing_key() {
+        let content = indoc! {"
+            home = /path/to/python
+            version = 3.8.0
+            include-system-site-packages = false
+        "};
+        let result = PyVenvConfiguration::set(content, "version", "3.9.0");
+        assert_eq!(
+            result,
+            indoc! {"
+                home = /path/to/python
+                version = 3.9.0
+                include-system-site-packages = false
+            "}
+        );
+    }
+
+    #[test]
+    fn test_set_new_key() {
+        let content = indoc! {"
+            home = /path/to/python
+            version = 3.8.0
+        "};
+        let result = PyVenvConfiguration::set(content, "include-system-site-packages", "false");
+        assert_eq!(
+            result,
+            indoc! {"
+                home = /path/to/python
+                version = 3.8.0
+                include-system-site-packages = false
+            "}
+        );
+    }
+
+    #[test]
+    fn test_set_key_no_spaces() {
+        let content = indoc! {"
+            home=/path/to/python
+            version=3.8.0
+        "};
+        let result = PyVenvConfiguration::set(content, "include-system-site-packages", "false");
+        assert_eq!(
+            result,
+            indoc! {"
+                home=/path/to/python
+                version=3.8.0
+                include-system-site-packages = false
+            "}
+        );
+    }
+
+    #[test]
+    fn test_set_key_prefix() {
+        let content = indoc! {"
+            home = /path/to/python
+            home_dir = /other/path
+        "};
+        let result = PyVenvConfiguration::set(content, "home", "new/path");
+        assert_eq!(
+            result,
+            indoc! {"
+                home = new/path
+                home_dir = /other/path
+            "}
+        );
+    }
+
+    #[test]
+    fn test_set_empty_content() {
+        let content = "";
+        let result = PyVenvConfiguration::set(content, "version", "3.9.0");
+        assert_eq!(
+            result,
+            indoc! {"
+                version = 3.9.0
+            "}
+        );
+    }
 }
diff --git a/crates/uv/src/commands/project/environment.rs b/crates/uv/src/commands/project/environment.rs
index a8c4110f0..ee4e9213f 100644
--- a/crates/uv/src/commands/project/environment.rs
+++ b/crates/uv/src/commands/project/environment.rs
@@ -150,6 +150,22 @@ impl CachedEnvironment {
         Ok(())
     }
 
+    /// Enable system site packages for a Python environment.
+    #[allow(clippy::result_large_err)]
+    pub(crate) fn set_system_site_packages(&self) -> Result<(), ProjectError> {
+        self.0
+            .set_pyvenv_cfg("include-system-site-packages", "true")?;
+        Ok(())
+    }
+
+    /// Disable system site packages for a Python environment.
+    #[allow(clippy::result_large_err)]
+    pub(crate) fn clear_system_site_packages(&self) -> Result<(), ProjectError> {
+        self.0
+            .set_pyvenv_cfg("include-system-site-packages", "false")?;
+        Ok(())
+    }
+
     /// Return the [`Interpreter`] to use for the cached environment, based on a given
     /// [`Interpreter`].
     ///
diff --git a/crates/uv/src/commands/project/run.rs b/crates/uv/src/commands/project/run.rs
index 9b77bfe08..6248634ab 100644
--- a/crates/uv/src/commands/project/run.rs
+++ b/crates/uv/src/commands/project/run.rs
@@ -25,8 +25,9 @@ use uv_fs::{PythonExt, Simplified};
 use uv_installer::{SatisfiesResult, SitePackages};
 use uv_normalize::PackageName;
 use uv_python::{
-    EnvironmentPreference, Interpreter, PythonDownloads, PythonEnvironment, PythonInstallation,
-    PythonPreference, PythonRequest, PythonVersionFile, VersionFileDiscoveryOptions,
+    EnvironmentPreference, Interpreter, PyVenvConfiguration, PythonDownloads, PythonEnvironment,
+    PythonInstallation, PythonPreference, PythonRequest, PythonVersionFile,
+    VersionFileDiscoveryOptions,
 };
 use uv_requirements::{RequirementsSource, RequirementsSpecification};
 use uv_resolver::Lock;
@@ -923,6 +924,21 @@ hint: If you are running a script with `{}` in the shebang, you may need to incl
             "import site; site.addsitedir(\"{}\")",
             site_packages.escape_for_python()
         ))?;
+
+        // If `--system-site-packages` is enabled, add the system site packages to the ephemeral
+        // environment.
+        if base_interpreter
+            .is_virtualenv()
+            .then(|| {
+                PyVenvConfiguration::parse(base_interpreter.sys_prefix().join("pyvenv.cfg"))
+                    .is_ok_and(|cfg| cfg.include_system_side_packages())
+            })
+            .unwrap_or(false)
+        {
+            ephemeral_env.set_system_site_packages()?;
+        } else {
+            ephemeral_env.clear_system_site_packages()?;
+        }
     }
 
     // Cast from `CachedEnvironment` to `PythonEnvironment`.
diff --git a/crates/uv/src/commands/tool/run.rs b/crates/uv/src/commands/tool/run.rs
index 6a057f5d7..e14ac1a9f 100644
--- a/crates/uv/src/commands/tool/run.rs
+++ b/crates/uv/src/commands/tool/run.rs
@@ -801,6 +801,7 @@ async fn get_or_create_environment(
 
     // Clear any existing overlay.
     environment.clear_overlay()?;
+    environment.clear_system_site_packages()?;
 
     Ok((from, environment.into()))
 }