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Over the past decade, overdoses involving opioids and benzodiazepines have risen at alarming rates, making reductions in coprescribing of these medications a priority, particularly among patients who may be susceptible to adverse events due to high-risk conditions.This quality improvement project evaluated the effectiveness of a medication alert designed to reduce opioid and benzodiazepine coprescribing among Veterans with known high-risk conditions (substance use, sleep apnea, suicide-risk, age 65 and above) at 1 Veterans Affairs (VA) health care system.Prescribers were exposed to the point-of-prescribing alert for 12 months. For each high-risk cohort we used interrupted time series design to examine population trends in coprescribing 12 months after alert launch adjusting for coprescribing 12 months before launch, demographics and clinical covariates. Trends at the alert site were compared with those of a similar VA health care system without the alert. Secondary analyses examined population trends in opioid and benzodiazepine prescribing separately.Over 12 months, the alert activated for 1332 patients. Proportions of patients with concurrent prescriptions decreased significantly postalert launch among substance use [adjusted odds ratio (AOR)=0.97; 95% confidence interval (CI)=0.96–0.99; 12-month decrease=25.0%], sleep apnea (AOR=0.97, 95% CI=0.95–0.98, 12-month decrease=38.5%), and suicide-risk (AOR=0.94, 95% CI=0.91–0.98, 12-month decrease=61.5%) cohorts at the alert site. Decreases in coprescribing were significantly different from the comparison site among suicide-risk (AOR=0.92, 95% CI=0.86–0.97) and sleep apnea (AOR=0.98, 95% CI=0.96–1.00) cohorts. Significant decreases in benzodiazepine prescribing trends were observed at the alert site only.Medication alerts hold promise as a means of reducing opioid and benzodiazepine coprescribing among certain high-risk groups.