© 2018 Ascend Media. All rights reserved. OBJECTIVES: To describe the prevalence and incidence of opioid and nonsteroidal anti-inflammatory drug (NSAID) use before and since the start of the Veterans Health Administration (VHA) Opioid Safety Initiative (OSI) and to assess rates of adverse events (AEs). STUDY DESIGN: Historical cohort study. METHODS: The OSI began in August 2012 and was fully implemented by the end of fiscal year (FY) 2013. The study timeframe was categorized into baseline (FY 2011-2012), transition (FY 2013), and postimplementation (FY 2014-2015) phases. Prevalence and incidence rates were calculated for opioid and NSAID users by quarter between FY 2011 and FY 2015. For AEs among new users of an NSAID or opioid, Cox proportional hazards models with inverse probability weighting were used to adjust for potential confounding. RESULTS: There were 3,315,846 regular users of VHA care with at least 1 opioid and/or NSAID outpatient prescription between FYs 2011 and 2015. The quarterly opioid prevalence rate was approximately 21% during the baseline and transition phases, then decreased to 17.3% in the postimplementation phase. NSAID prevalence remained constant at about 16%. Opioid incidence rates gradually decreased (2.7% to 2.2%) during the study, whereas NSAID incidence rates remained about 2.2%. After inverse probability weighting, patients receiving opioids had a greater risk of cardiovascular events (hazard ratio [HR], 1.41; 95% CI, 1.36-1.47), acute kidney injury (HR, 2.60; 95% CI, 2.51-2.68), gastrointestinal bleeding (HR, 1.68; 95% CI, 1.56-1.81), and all-cause mortality (HR, 3.73; 95% CI, 3.60-3.87) than NSAID users. CONCLUSIONS: Opioid use declined following implementation of the OSI, whereas NSAID use remained constant. Rates of AEs were higher among opioid users, which provides additional rationale for efforts to use NSAIDs for pain management when appropriate.