Drug overdose mortality nearly doubled in the United States from 1999 to 2004, with most of the increase due to prescription drug overdoses. Studying mortality rates in states that did not experience such increases may identify successful prescription overdose prevention strategies. We compared New York, a state that did not experience an overdose increase, with its neighbor, Pennsylvania. New York and Pennsylvania had prescription drug monitoring programs (PDMPs), but New York's PDMP was better funded and made use of serialized, tamperproof prescription forms. Per capita usage of the major prescription opioids in New York was two-thirds that of Pennsylvania. The drug overdose death rate in Pennsylvania was 1.6 times that of New York in 2006. Differences between New York and Pennsylvania might be due to the regulatory environment in New York State.