To examine the impact of prescription drug monitoring programs (PDMPs) on drug overdose deaths.We used variation in the timing of state PDMP legislation and implementation to estimate the impact of these programs on drug overdose mortality rates across all drug categories from 1999 to 2014 and separately for each category from 1999 to 2010. Data used include US all-jurisdiction mortality data, estimated population data, and sociodemographic data from the CDC and the US Census Bureau.Multivariate regression models were applied to state panel data, including state and year fixed effects and state-specific linear time trends. Preprogram tests were used to assess the common trends assumption underlying our empirical approach.The implementation of PDMPs was not associated with reductions in overall drug overdose or prescription opioid overdose mortality rates relative to expected rates in the absence of PDMPs. For most categories, PDMPs were associated with increased mortality rates, but the associations were statistically insignificant. In a subsample analysis of states with PDMPs in operation for 5 or more years, the programs were found to be associated with significantly higher mortality rates in legal narcotics, illicit drugs, and other and unspecified drugs.PDMPs were not associated with reductions in drug overdose mortality rates and may be related to increased mortality from illicit drugs and other, unspecified drugs. More comprehensive and prevention-oriented approaches may be needed to effectively reduce drug overdose deaths and avoid fatal overdoses from other drugs used as substitutes for prescription opioids.