A few things to consider...
If you haven't already, open Windows Explorer and main menu Tools | Folder Options | View, select the Show Hidden Files radio button and untick the Hide protected operating system files checkbox. Then go back and look to see where the big files are. Some may be in c:\, namely hibernation files (hiberfil.sys) and / or virtual memory (pagefile.sys). These should not account for all the seemingly unavailable space, but it's possible they account for a good chunk of it.
Re virtual memory, verify Windows doesn't have your virtual memory set to some ludicrous size. It's happened to me before - it just kept growing, and growing, and growing... Settings | Control Panel | System applet, Advanced tab. In the Performance section, press the Settings button, navigate to the Advanced tab, and in the Virtual Memory section, press the Change button. Make sure the Paging File Size is reasonable, say...1x or 1.5x your RAM for starters.
Maybe install a freeware app that will search the entire drive and show you the size of each individual directory. Maybe the directories are hidden (and the first comment above should help with that), maybe you're just missing it if it's a PITA to manually check every one.
Just guesses at this point. Can you show us a screenshot of the drive in Computer Management | Disk Manager?