If you are running in an environment with lots of small-sized files then each one of these files could be occupying larger sectors on the disk than it needs. You may want to look into changing to FAT32 if you haven't done it already.
If you or your system is constantly modifying data, then there could be fragmentation problems. Run scandisk, then defrag.
Of course, don't discount a virus doing odd things either. Run an up-to-date virus scanner.
Another check is to check the size of your recycle bin. There is an option to limit the size of your recycle bin, but this is a percentage of the entire drive, not an MB value. If you have lots of files deleted, you can set a smaller percentage size or to delete files immediately instead of putting them in the recycle bin.
Hope that helps,