The only time I managed to slow down one of my systems was when I copied 80,000 photos to the C: drive while I was doing other things at the same time. System startup was noticably slower afterwards and the system sometimes felt sluggish.

I figure that when the mass of photo files was being created some other important files being created or extended at the same time got fragmented and slowed down the system (anti-virus??). I transferred the photo files to an external drive, defragmented the C: drive and all went back to normal.

I never let my C: drive go over 75% full so that the defragmenter has lots of space to work with. I never install more than the bare minimum of software that I actually need. And I disable unnecessary background tasks (like software that does a popup when I put a CD in the drive)

Afterthought for the other techos out there:
I was going to put "anti-virus?? pagefile??" but then I always have a fixed-size pagefile to avoid fragmentation, don't I?
Well I checked on the portable I'm using (I'm in Budapest right now) and NO the pagefile is set by the system and even worse it's trimmed the size down to 3GB instead of the recommended 4.3GB (this is a 4GB Vista machine). AGH. At least the disk is defragmented every night.
But finally - all I'm doing here is some web browsing, Lightroom, ACDSee, one after the other, nothing complex. I probably never go over 3GB of RAM used anyway. Maybe the system does know what it's doing after all...
Opinions?