Very interesting topic. Over the years I've acquired a lot of preferred settings. I always change the following, if possible:
-Inverted Mouselook = on
I can't play shooters without inverting the mouse.
For whatever reason, I can't play console shooters with the stick inverted. I've got a friend who's the exact opposite! Can't play PC FPS with inverted controls but always turns it on when playing an FPS on the PS3 or 360.
This is probably the weirdest thing because I have different preferences on different platforms.
-VSync = on
I hate even minor screen tearing, so I turn it on.
-WASD Controls and some other things. I usually swap space (use) with rmb (jump), which often confuses people playing with my settings.
-AF to me is much more important than AA, so I put the former pretty high while the latter can easily be on just 2x (don't like playing without though)
-I hate motion blur, but like bloom for some weird reason. All the other filters don't really do anything for me. I leave them on if they don't cost too much performance.
-real fullscreen, never windowed. I hate windowed mode because it reduces the immersion for me
-increase (or decrease) the graphics details so I get at least 30fps. Running at native resolution is very important and I rather keep a high texture resolution and turn off other stuff. graphics aren't that important to me, I just don't like blurry textures and display scaling.
-difficulty to the highest and if it's too hard I reduce it to the normal level at most. Never play on easymode
-subtitles off, I've got ears for that. Subtitles tend to make me slightly impatient and skip the dialogue and I don't like that
-toggle stand/crouch & run/walk instead of hold. The first one is DeusEx' fault, because I was constantly sneaking around while crouching and holding the key down gave me cramps.
-I always (if the soundtrack is good) turn up the music (and if possible ambient sfx) and lower the overall game volume. Speech is somewhere in between, where it's still audible. I could never understand how people were able to play games like doom, deus ex, diablo and other titles which have great soundtracks with the music turned way down or even off. The soundtrack of a game is really important to my enjoyment of the game. If I can't hear the music because my gun is too loud I reduce the sfx volume.
That's all I can think of for now. There are a LOT of game specific settings, but going through all of those would take up too much time 😉