Metal Gear Solid 2: Substance, the expanded edition of the game, was released on the original Xbox and Windows in addition to the PlayStation 2. The Xbox version was initially released in North America as a timed exclusive for the console on November 5, 2002. This was followed by the PlayStation 2 version, released in Japan on December 19 of the same year. Substance was eventually released on PlayStation 2 and Windows in North America and on all three platforms in Europe in March 2003. The console versions were developed internally by KCE Japan, whereas the Windows port was outsourced to Success.

Substance contains several supplemental game modes in addition to the main story mode from the original Sons of Liberty releases. The main game contains all the changes and additions that were made in the Japanese and European versions of the original release (e.g., Boss Survival, Casting Theater, European Extreme), along with further additional changes. Players can now start the main story mode at the Tanker or Plant chapters without the need to answer a questionnaire first, and a new set of collectible dog tags have been added (exclusively on the PlayStation 2 version) based on names submitted from a second contest in addition to the original (2001) set. The visual effect for the thermal goggles was also changed in Substance, and the FHM-licensed posters that adorned several locations in the original Sons of Liberty version have been replaced with public domain images (these were also replaced in The Document of Metal Gear Solid 2). The Xbox and Windows versions feature slight dialogue changes during specific control explanations in which the term "analog stick" was substituted with "thumbstick" (Microsoft's preferred term). The controls were also slightly altered for the Xbox version, due to its fewer shoulder buttons (clicking on the left thumbstick switches between normal and first-person view, while the Y button serves as a lock-on for the player's aim). The Xbox version has support for 5.1 surround sound.