I usually have had great success against lefties except at the USTA Nationals where I lost a close match because it took me two sets to figure out what to do when a lefty hits an american twist serve. Actually I was leading the first set 5-3 and hit what I thought was a backhand passing shot for a winner on set point. The crowd was cheering and after the cheering died down, the opponent informed me that my shot was out. Even though he had clipped me, I was not worried and built a 5-3 lead in the tiebreaker only to blow that lead and lose the set. Next I was up 40-0 in my first service game of the second set and wound up losing that game for the only break of the set. However when he was serving for the set at 5-4 and 40-love I finally figured out how to return his American Twist service for outright winners. I had been taking it with my backhand but realized that if I took it with my forehand it would merely be the same are return a righty slice serve or topsin serve. I proceeded to pass him on the first two returns to make the score, 40- 30, then on the last set point I hit another great shot but he lunged for it and made a miracle volley for a winner. After the match was over, my opponent told me that he couldnt believe that he had beaten me. I felt like telling him that as long as he keeps up the cheating in set points, he should continue to do well!
Anyway, normally I play well against lefties. The key is to slice the serve either to their backhands or else slice it into their bodies. Also pull them off the court with crosscourt forehands to their backhands. then either hit behind them or to the open court. But mainly its how you return their serves that makes the difference and how you serve to them.