This normally happens if you load a fullscreen application on your first monitor that isn't using it's native resolution. For example..
I run two screens; a 24" as my first and 22" as my second.
If I run a game (first screen) I MUST run it at 1920x1080 to view my second screen correctly. If I run something on my first screen at say 1440x900, my second screen shows at a larger resolution.
Do you run games at 1440x900 when you play them?