You talking about an 1858 Remington-style revolver?
On my Pietta .31 caliber Pocket Remington there's no question, because the safety notches don't work. The pocket model's a five-shooter too, so leaving one chamber unloaded means only FOUR shots.
But that doesn't bother me too much, since a .31 cap and ball is not exactly my first choice for self-defense.
I used to have Colt replicas that had a "safety pin" between the chambers. That thing looked awfully weak. I didn't trust it and never used it, except to try it a couple of times with an unloaded revolver to see how it worked.