It depends on your Window Layout, and how your GPUs are (or are not) linked together via SLI/Crossfire. See GPU Management
. For performance tips, see HOWTO: Tweak your framerate
I'm GUESSING that you have your 6950's in Crossfire mode, and are comparing one full screen instance of Diablo 3 without ISBoxer (using all 3 GPUs), to 4 windowed instances of Diablo 3 (and it ends up using 1 of the GPUs). This is discussed in the GPU Management article, under "SLI and Crossfire modes". The first thing I would do is check for driver a update, because whether or not Crossfire works in windowed mode is a driver thing. The article also recommends to disable Vertical Sync, so if that's enabled in the game, turn it off and that may correct the problem. Past that, see the framerate tweaking article
Catalyst Control Center can also be closed, or you can try disabling Catalyst AI (I think the name changed... it's something about application-specific profiles)
If you want more assistance with your GPUs, be specific as to what monitor is plugged into what card and whether you have Crossfire enabled, and show me your ISBoxer config HOWTO: Share your configuration for better support
And yes, it is possible to have different graphics settings in each window, using a Virtual File for the game's graphics settings file. For Diablo 3 that is "D3Prefs.txt", here's how to do it:
1. In the top left pane in ISBoxer, right click Virtual Files and select New Virtual File
2. This created a Virtual File that is literally named "New Virtual File". Right click that and select Rename, and type in, or paste, "D3Prefs.txt" with no quotes.
3. Under Virtual Files in the top left pane, select (highlight) D3Prefs.txt, so you see it come up for editing in the bottom left pane
4. Drag (but do not select/highlight) Characters from the top left pane under Characters, to the bottom left pane under Characters. Each one will automatically get its own filename to replace D3Prefs.txt
5. Export to Inner Space.
You can then change any of the settings in the game on a per-window basis, and you will have files in My Documents\Diablo III for each of your ISBoxer "Characters" that you can manually edit.
That should help.