I haven't tried to run
WordPress MU or set up a "WordPress Network" on my sites, which is what I assume you're referring to for the multi-site/one-install deal, however I am running WordPress on one of my main sites and running it on an IRM under that main as well. I just did two separate installations, and they are using two separate themes.
WordPress is pretty
simple to install and, once it's up, it's really easy to maintain now with their one-click updates (wasn't always the case).