I kept getting an intermittent "There is no disk in the drive" popup and it became annoying enough that I fixed it. I'm probably not the first one to figure this out, but I haven't seen a solution to this problem yet so here's what I did:

My Setup:
1) Windows 8 x64
2) Old Athlon 6000 X2 x64
3) Radeon HD3800

Notes:
1) This is a "duct tape" fix - i.e. it is not elegant, it doesn't involve modifying the code with a hex editor, it has nothing to do with programming really, it's a relatively simple batch file
2) It came about because I read on this forum and others that NwN doesn't play well with USB storage devices.
3) Disabling the USB storage devices through the device manager, running the program, and reenabling the USB storage devices worked every time.
4) That was tedious so I wrote a batch file to do it for me. :)

What you need:
1) Put Devcon.exe (I can't post links yet so google it) in your NwN installation directory
2) Put PSTools (I still can't post links so google it) in your NwN installation directory
3) Create "runme.bat" as follows (you'll see I also had to rename nwmain.exe)

devcon disable *USBSTOR\*
nwmain_.exe
devcon.exe enable *USBSTOR\*

4) Create a shortcut to psexec and use the following:

Target: "<<installation directory>>\PsExec.exe" runme.bat
Start In: "<<installation directory>>
Check "Run this program as an administrator" in the Compatibility tab.

It needs to run in admin mode to get the devices properly disabled. If you don't run it in admin mode, it will report that the devices have been disabled, but they really haven't.

This won't work if you have NwN installed on a USB storage device. :)

Hope this works for you - it works for me every time!
Jeff.

Or you could run a version 1.69 critical rebuild and fix it permanently.

Yeah, thing is...that didn't work. It still asked me to insert the disk. And on drive N: which is the last enumerated unmounted USB storage disk I have. I used device manager to disable "N:" and then NwN asked for a disk in drive "L:". All that behavior was exactly the same both before and after installing the critical update patch.

Mea Culpa. I should have read your post a little more closely.

I'm glad you found a fix. Best practice is to install the game right on your hard drive.

Yeah, that wasn't at all clear from my post. Sorry about that. I had heard that well after the fact. I should try installing it on the C drive instead of a different hard drive. I wonder if that would work better? Currently, I have a "games" partition on one of my hard drives that I install all my games on. Maybe I'll try installing it on the "C" drive. But my C drive is an SSD and I don't like to fill it up too much.

Actually the issue does not seem to be that the game is installed on USB. If you have a large USB device plugged in it freaks the game out. I had to unplug my USB drive for it to work.