OS rot is a common problem in older versions of Microsoft Windows. Over time, the installation and removal of programs causes a buildup of DLLs and registry entries to occur, which is more stuff for Windows to muddle through when trying to get a value or decide what to load. Windows XP seems to deal with OS rot a bit better, however, with the advent of spyware and the tons of worms and malicious code floating around, symptoms of OS rot are still around.

What can be done to prevent OS rot and general system slowness?

Don't install loads of programs you'll never use
This is a big one. If you install a lot of software that you'll never use, you're just adding to the pile of DLLs and registry entries in addition to taking up your disk space.

Keep your antivirus up to date
Keeping your antivirus software up to date protects your machine from attack. If a virus gets into your machine, it will not only start acting weird, it will also slow down.

Run a spyware cleanup program
Spyware is a big culprit when it comes to system slowdowns. Run something such as AdAware or Spybot Search and Destroy to clean up any spyware that you have.

Defragment your hard drive
Over time as you delete and create files, your hard drive becomes fragmented. As fragmentation becomes worse, the drive has to search all over the disc to find files, and that takes time. Defragmenting pulls all of these file fragments back together, and usually helps keep the machine running smoothly

If any of the above solutions don't work, or your machine is just returning a lot of errors, it may be time to backup your data and reformat the machine. This is a pretty harsh step, but sometimes it's the only way to fix the problems that occur with OS decay.

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