OBJECTIVES:  The aim of this study was to determine if state-based mandates for prescribers to query the Prescription Drug Monitoring Program (PDMP) before prescribing controlled substances is associated with decreased opioid and drug-related adverse events. METHODS:  Four states newly implemented a PDMP mandate in 2013 providing a natural experiment. Pharmacy claims and medical service data were analyzed from a 10% random sample of the IMS LifeLink Pharmetrics+ database between 7/1/11 to 12/31/14 for persons using opioids or benzodiazepines. A retrospective difference in difference study design was employed to contrast changes in adverse events (AE) between PDMP mandate states (n=4) and 16 states with PDMP programs without mandates. A composite AE measure consisted of: (i) opioid dependence, abuse, and poisonings (ii) non-opioid drug-related overdoses and poisonings (iii) prescription fills for Suboxone or naloxone. Cox Proportional Hazard modeling was used to estimate the relative risk of AEs until subjects experienced an AE, lost enrollment, or study end. RESULTS:  For pre and post periods respectively, 54,079 and 58,992 patients met inclusion criteria in mandate states with 100,475 and 114,888 patients in non-mandate states. In mandate states, 67.6% used opioids exclusively compared to 65.2% in non-mandate states. Composite AE rates were higher for the mandate states (7.87 and 10.03 AEs per 1000 person-years pre and post respectively) as compared to the non-mandate states (6.73 and 7.16 AEs per 1000 person-years). In fully adjusted models, states that implemented the mandate had higher baseline risks of AEs (HR=1.26, 95%CI: 1.15-1.37) and AEs increased between 2012 and 2014 (HR=1.12, 95%CI: 1.03-1.22) but there was no significant effect of state mandate (HR=1.03, 95%CI: 0.86-1.20). Sensitivity analyses showed similar findings. CONCLUSIONS:  States that implemented PDMP mandates had higher rates of AEs in 2012; however, PDMP mandates were not associated with changes in AEs related to opioids and benzodiazepine use.