I had a two shot derringer in the early 1980s. It was chambered for .22 magnum. But I always called it my "one shot" derringer because of all the times the ammo failed.

Rim fire ammo will never be as reliable as centerfire ammo, although they seem to be better at it in 2012 than they were in 1982.

A .38 in a jacketed soft point lead would be my choice. I don't know if anyone is making a true defensive round in soft point, but that is what I'd look for.