Window-Eyes is the second most used screen reader. If you’re trying to insure 508 compliance this is probably the way to go since Jaws is the screen reader used by the US government. You can download a demo of it that will run for 40 minutes at a time then require you to reboot if you want to run it again. Jaws is the most widely used screen reader out there. One issue with NVDA is the fact that its accessibility is only really good in Firefox so you'll have to use that to test. I'd say if a site works with NVDA it's likely to work with most other screen readers.

It isn't quite as good as some of the commercial screen readers out there but it gets the job done. NVDA is an open source screen reader that is rather new.

In summary if you want to make sure your site is mostly accessible use NVDA, if you want to make sure that blind individuals working in the government will be able to use your site use Jaws to test, if you want to be extra safe use Window-Eyes and Orca to test as well. Note this is a rather long post so I’ve summarized it at the top.

I'm a totally blind individual so comments on screen readers are below. Just because something meets the guideline doesn't mean it's guaranteed to be accessible, all screen readers have there different quirks.

Free accessibility screen reader