Coelocanth: I own F3 as well and you can play without the disc in the drive if you launch the game directly from the .exe. Don't use the launcher. Not sure if this still works with the GOTY edition, but it does with the original release.
It does. I have the GotY edition and it runs fine from the .exe instead of the launcher. I only had to put the disk in the drive to play once, and that was after a hardware change, as it apparently was forcing the launcher to run. After the launcher ran once, it went back to working as expected from the .exe, and has continued to do so since. I use FOMM to launch the game, though, so I'm not sure if that makes any difference.
I'd be interested to get a steam-free version of FONV, but I wouldn't be soiling my undergarments or anything over it.