Whats the "safest" way to clean up large files in the Windows Installer cache? Is deleting the files the only way, or is there a better way to "unregister" the cached files or something?
You'll want to be careful about this. The cached installation packages may be necessary for installing application patches, uninstalling certain applications, or repairing applications and the OS.
However, if your computer is running well at this point and having more free HDD space is more important than being able to remove patches or repair applications, then CCleaner is the tool you'll want to use.
In Windows XP, in the Cleaner tool in CCleaner, in the Windows tab, 3rd from last option should be "Hotfix Uninstallers".
In Windows 7 you cannot remove the OS patch cache because it isn't really quite the same thing anymore and cannot be handled the same way. But it also doesn't store nearly as much info. If you hadn't noticed, Windows 7 patches tend to be much smaller than comparable WinXP patches due to efficiencies developed in the patching system for 7.