Same problem here, except I'm using PHP 4.0.5 with IIS on Win2k, and MySQL 3.23.38. When I'm doing development work and testing new pages, it doesn't take long (10-15 minutes) before I get the Internal Server Error (500) pages, and then I have to reboot my machine to make it work again.
It doesn't happen when I use stable pages, like Hello-World pages, only when I'm working on new things. After a buggy page or two, PHP simply quits working. Stopping & restarting IIS doesn't make a difference, either.
The only odd configurations I have are that the web root is on my C drive, and PHP & everything else is on my F (system) drive. Other than that, it's pretty straightforward.