diff --git a/crates/ruff_linter/resources/test/fixtures/pycodestyle/E402_5.py b/crates/ruff_linter/resources/test/fixtures/pycodestyle/E402_5.py
new file mode 100644
index 0000000000..f4554f78ea
--- /dev/null
+++ b/crates/ruff_linter/resources/test/fixtures/pycodestyle/E402_5.py
@@ -0,0 +1,19 @@
+# Issue: https://github.com/astral-sh/ruff/issues/16247#event-16362806498
+
+import os
+import site
+import sys
+import sysconfig
+
+site.addsitedir(
+    os.path.join(
+        os.path.dirname(os.path.dirname(__file__)),
+        sysconfig.get_path("purelib", vars={"base": "."}),
+    )
+)
+
+from mypkg.__main__ import main
+
+if __name__ == "__main__":
+    sys.argv[0] = sys.argv[0].removesuffix(".py")
+    sys.exit(main())
\ No newline at end of file
diff --git a/crates/ruff_linter/src/checkers/ast/mod.rs b/crates/ruff_linter/src/checkers/ast/mod.rs
index f34bc44029..e09405250f 100644
--- a/crates/ruff_linter/src/checkers/ast/mod.rs
+++ b/crates/ruff_linter/src/checkers/ast/mod.rs
@@ -556,7 +556,8 @@ impl<'a> Visitor<'a> for Checker<'a> {
                     || imports::is_matplotlib_activation(stmt, self.semantic())
                     || imports::is_sys_path_modification(stmt, self.semantic())
                     || imports::is_os_environ_modification(stmt, self.semantic())
-                    || imports::is_pytest_importorskip(stmt, self.semantic()))
+                    || imports::is_pytest_importorskip(stmt, self.semantic())
+                    || imports::is_site_sys_path_modification(stmt, self.semantic()))
                 {
                     self.semantic.flags |= SemanticModelFlags::IMPORT_BOUNDARY;
                 }
diff --git a/crates/ruff_linter/src/rules/pycodestyle/mod.rs b/crates/ruff_linter/src/rules/pycodestyle/mod.rs
index 84b3363f10..a6a2180bbb 100644
--- a/crates/ruff_linter/src/rules/pycodestyle/mod.rs
+++ b/crates/ruff_linter/src/rules/pycodestyle/mod.rs
@@ -45,6 +45,7 @@ mod tests {
     #[test_case(Rule::ModuleImportNotAtTopOfFile, Path::new("E402_2.py"))]
     #[test_case(Rule::ModuleImportNotAtTopOfFile, Path::new("E402_3.py"))]
     #[test_case(Rule::ModuleImportNotAtTopOfFile, Path::new("E402_4.py"))]
+    #[test_case(Rule::ModuleImportNotAtTopOfFile, Path::new("E402_5.py"))]
     #[test_case(Rule::ModuleImportNotAtTopOfFile, Path::new("E402.ipynb"))]
     #[test_case(Rule::MultipleImportsOnOneLine, Path::new("E40.py"))]
     #[test_case(Rule::MultipleStatementsOnOneLineColon, Path::new("E70.py"))]
diff --git a/crates/ruff_linter/src/rules/pycodestyle/snapshots/ruff_linter__rules__pycodestyle__tests__E402_E402_5.py.snap b/crates/ruff_linter/src/rules/pycodestyle/snapshots/ruff_linter__rules__pycodestyle__tests__E402_E402_5.py.snap
new file mode 100644
index 0000000000..81d49b4bba
--- /dev/null
+++ b/crates/ruff_linter/src/rules/pycodestyle/snapshots/ruff_linter__rules__pycodestyle__tests__E402_E402_5.py.snap
@@ -0,0 +1,3 @@
+---
+source: crates/ruff_linter/src/rules/pycodestyle/mod.rs
+---
\ No newline at end of file
diff --git a/crates/ruff_python_semantic/src/analyze/imports.rs b/crates/ruff_python_semantic/src/analyze/imports.rs
index 19802a8092..60313eba14 100644
--- a/crates/ruff_python_semantic/src/analyze/imports.rs
+++ b/crates/ruff_python_semantic/src/analyze/imports.rs
@@ -127,3 +127,23 @@ pub fn is_pytest_importorskip(stmt: &Stmt, semantic: &SemanticModel) -> bool {
             matches!(qualified_name.segments(), ["pytest", "importorskip"])
         })
 }
+
+/// Returns `true` if a [`Stmt`] is a dynamic modification of the Python
+/// module search path, e.g.,
+/// ```python
+/// import site
+///
+/// site.addsitedir(...)
+/// ```
+pub fn is_site_sys_path_modification(stmt: &Stmt, semantic: &SemanticModel) -> bool {
+    if let Stmt::Expr(ast::StmtExpr { value, .. }) = stmt {
+        if let Expr::Call(ast::ExprCall { func, .. }) = value.as_ref() {
+            return semantic
+                .resolve_qualified_name(func.as_ref())
+                .is_some_and(|qualified_name| {
+                    matches!(qualified_name.segments(), ["site", "addsitedir"])
+                });
+        }
+    }
+    false
+}