I seem to recall answering a similar topic earlier, but whatever...
If I had to choose just one game to be my all-time favorite, it would be between
Cave Story and
Doom 2. I enjoy both of these games for very different reasons. On one hand, I prefer
Cave Story in terms of characters, story, music, alternate paths and endings. On the other hand, I really like
Doom 2 for its combat, exploration, and the setting. Not to mention the outstanding mods for both games!
I think as a stand alone game, I would choose
Cave Story. But if modding was taken into consideration, then
Doom 2 would be my top pick!