It just does. I can't stare at it for more than 5 minutes. Nothing I play is full screen.
You're probably playing at 60Hz. 75Hz is pretty standard and causes me no eye strain. However, I can see 60Hz "flickering" and it quickly begins straining my eyes and typically gives me a headache. You've probably got your desktop resolution/bit-depth set up with 75 or higher, but in-game, it's going back to 60. Your monitor usually shows the current refresh rate in the settings somewhere; it is typically different for each resolution.
You can change the refresh rate under your windows monitor settings, and if you have trouble with that, can try something like ReForce to set it (although ReForce does small things like causing Battlefield 2 to not start up).
edit: Yes, windowed does have its advantages. I play all my Source games windowed just because it gives me a few more FPS (I play them at widescreen so the task bar just fits in perfectly) and I can easily open up firefox or something while a map is downloading.