Independent bookstores need to be masters of niche marketing. The lefty bookstores will always thrive in college towns, etc. Used book stores seem to do well because folks want to turn over their own stock of books from time to time. I'd think a combination of new and used would be a good one, selling some 'hot new authors' as well as new editions of the classics, along with used books.
"The lefty bookstores will always thrive in college towns, etc"
I've often thought someone should open one catering to "righty's". Might work...might not but it's worth a try.