First of all let's make sure there isn't a simple problem causing issues here: Make sure your mirc.ini isn't set to read-only. It's unlikely to be the cause but we might aswell make sure before we move onto anything more involved.
A far more likely problem is Vista's folder virtualisation messing with mIRC's ability to write to the file and read the same information back. I know you've said you've got write access to it but that's not necessarily going to stop Vista from quietly deciding it knows better than you.
I'd strongly suggest setting up your mIRCs to store their settings somewhere outside of your Program Files directory. Either use the -r switch to tell mIRC to store the files elsewhere (eg, a subdirectory of your user directory) or install mIRC outside of Program Files (eg. C:\mIRC) and put a mirc.ini in that folder.
I'm confident this will fix all your problems. Even if it doesn't it will remove the most likely suspect from the list and help find the true problem.
By the way I don't think there's any need to run mIRC in XP compatability mode. It might even hinder mIRC's ability to recognise that it's running in Vista and compensate for virtualisation.
