The Colt Python is the most accurate handgun and the only revolver available in the GTA series. It also shares the record for being the most powerful handgun with the Desert Eagle, although the Desert Eagle edges it out, being a .50AE instead of a .357.
"Dangerous peace-maker. One shot certain put a man down. Approach with extreme caution."
―GTA Vice City Website.
The Colt Python was first seen in Grand Theft Auto: Vice City. The gun cannot be fired while running, and must be fired from a standing position (grasping the butt of the gun with the right hand, then cradling the right hand and gun with the cupped left hand, all while planting feet at a wide stance) due to the heavy recoil of the .357 Magnum cartridge. It also has a moderate cylinder capacity of 6 shots, making it excellent against small groups. The Python is also available in Grand Theft Auto: Liberty City Stories, and the version in Grand Theft Auto: Vice City Stories (named Equalizer) features a laser scope and a 6" barrel, although the scope cannot be used.
The Colt Python is also a weapon in Grand Theft Auto: Chinatown Wars, and was named the Revolver. Although it cannot be visibly seen in the game, a HUD image of the weapon can be seen on the touch screen and on the Ammu-Nation website (strangely, it resembles a snub-nosed .38 Smith and Wesson or a Colt Detective Special).
Rockstar Games renamed the Colt Python to .357 in later versions of GTA Vice City, possibly to avoid copyright and trademark infringements.
In GTA Liberty City Stories, the spent shells are ejected while firing, which is impossible for any revolver.
Though the weapon itself doesn't appear in GTA San Andreas, the model from GTA Vice City is used for the giant Python at the entrance of the Los Santos Ammu-Nation.
The name Equalizer may be a reference to the Modesty Blaise comic "Top Traitor" as Modesty hands Tarrant a gun of similar model she mentions it will be a great equaliser.
However, it could also be a reference to the saying "God made man, Samuel Colt made them equal".
The scope on the python in GTA Vice City Stories may be visually inspired from a gun used in the movie "The Terminator" also set in 1984 although the movie was in Los Angeles not Miami (Vice City) and the gun from the movie was actually an AMT Hardballer (clone of the Colt M1911) rather than a revolver.
In GTA Vice City, there is a little glitch that can be triggered. If the player fires the Python while pressing the move left and move right buttons, Tommy will stick his knees together, but after the firing animation ends, he will also stick his legs to next to each other, and then will slowly return to his normal position (Tested on PC).
Within GTA: Vice City game files, the model and the texture files of a shorter Python exist. It's still unknown if the gun was additional or not.
The Chinatown Wars description of the gun is a reference to Dirty Harry.