diff --git a/wp-includes/plugin.php b/wp-includes/plugin.php
index f5d213d356..33e8963e57 100644
--- a/wp-includes/plugin.php
+++ b/wp-includes/plugin.php
@@ -638,16 +638,30 @@ function plugin_basename( $file ) {
  * This is used in {@see plugin_basename()} to resolve symlinked paths.
  *
  * @param string $file Known path to the file.
+ * @return bool Whether the path was able to be registered.
  */
 function wp_register_plugin_realpath( $file ) {
 	global $wp_plugin_paths;
 
+	// Normalize, but store as static to avoid recalculation of a constant value
+	static $wp_plugin_path, $wpmu_plugin_path;
+	if ( ! isset( $wp_plugin_path ) ) {
+		$wp_plugin_path   = wp_normalize_path( WP_PLUGIN_DIR   );
+		$wpmu_plugin_path = wp_normalize_path( WPMU_PLUGIN_DIR );
+	}
+
 	$plugin_path = wp_normalize_path( dirname( $file ) );
 	$plugin_realpath = wp_normalize_path( dirname( realpath( $file ) ) );
 
+	if ( $plugin_path === $wp_plugin_path || $plugin_path === $wpmu_plugin_path ) {
+		return false;
+	}
+
 	if ( $plugin_path !== $plugin_realpath ) {
 		$wp_plugin_paths[ $plugin_path ] = $plugin_realpath;
 	}
+
+	return true;
 }
 
 /**
diff --git a/wp-settings.php b/wp-settings.php
index aee35b3e9c..9f73195023 100644
--- a/wp-settings.php
+++ b/wp-settings.php
@@ -168,7 +168,6 @@ $GLOBALS['wp_plugin_paths'] = array();
 
 // Load must-use plugins.
 foreach ( wp_get_mu_plugins() as $mu_plugin ) {
-	wp_register_plugin_realpath( $mu_plugin );
 	include_once( $mu_plugin );
 }
 unset( $mu_plugin );