The Veterans Health Administration (VHA) designed the Opioid Safety Initiative (OSI) to help decrease opioid prescribing practices associated with adverse outcomes. Key components included disseminating a dashboard tool that aggregates electronic medical record data to audit real-time opioid-related prescribing and identifying a clinical leader at each facility to implement the tool and promote safer prescribing. This study examines changes associated with OSI implementation in October 2013 among all adult VHA patients who filled outpatient opioid prescriptions. Interrupted time series analyses controlled for baseline trends and examined data from October 2012 to September 2014 to determine the changes after OSI implementation in prescribing of high-dosage opioid regimens (total daily dosages >100 morphine equivalents [MEQ] and >200 MEQ) and concurrent benzodiazepines. Across VHA facilities nationwide, there was a decreasing trend in high-dosage opioid prescribing with 55,722 patients receiving daily opioid dosages >100 MEQ in October 2012, which decreased to 46,780 in September 2014 (16% reduction). The OSI was associated with an additional decrease, compared to pre-OSI trends, of 331 patients per month (95% confidence interval [CI] −378 to −284) receiving opioids >100 MEQ, a decrease of 164 patients per month (95% CI −186 to −142) receiving opioids >200 MEQ, and a decrease of 781 patients per month (95% CI −969 to −593) receiving concurrent benzodiazepines. Implementation of a national health care system-wide initiative was associated with reductions in outpatient prescribing of risky opioid regimens. These findings provide evidence for the potential utility of large-scale interventions to promote safer opioid prescribing.