The best setting is the one that sounds best to you, IMO, but here's some suggestions.
You'd want to use a sub if it can produce low frequencies better than your speakers. If it can, then you'd want to set your speakers to small so that the bass was handled by your sub.
Also, you'd want to pick a crossover frequency that was higher than the low-end of your speakers and lower than the high-end of your sub. A crossover of 80 Hz is a good starting point and is the recommended setting by THX, but you can tailor it for your system (if your receiver is capable of setting different crossover frequencies - some can, some can't).
If you let us know which speakers, sub, and receiver you have, then we can give more specific suggestions.