Defrag and disk space are not your problems. What is far more likely is either the 44/48 problem already mentioned, or possibly some bad file directory structure. Defrag often seems to make a difference -- even though it is a waste of time -- because to do a defrag first requires that the system do a chkdsk. Thus, you can get the benefit of the chkdsk but simply running that on all your drives. Also, make sure to empty all your Internet cache files (if you use multiple browsers, like Firefox and Opera, make sure to empty those as well). What happens, even with NTFS, is that the directory structure gets "clogged" with tens of thousands of files. This is not defragmentation, but instead is a database issue where the overhead of finding the file and sectors you want takes more time as the amount of "stuff" in the directory gets large.

So, do a chkdsk and flush the Internet cache the next time this happens and see if that doesn't fix your problem. Takes only a few minutes (unlike the defrag which can hammer your disk for hours).