Objectives: This prospective cohort study examines the clinical effectiveness of electronic medical record clinical decision support (EMR CDS) for opioid prescribing.; Methods: Data analysis included primary care patients with chronic opioid therapy for noncancer pain seen within an integrated health delivery system in Louisiana between January 2017 and October 2018. EMR CDS incorporated an opioid health maintenance tool to display the status of risk mitigation, and the medication order embedded the morphine equivalent daily dose (MEDD) calculator and a hyperlink to the Louisiana pharmacy drug monitoring program. Outcome measures included change in the average MEDD and rates of opioid risk mitigation, hospitalization, and emergency department use.; Results: Among 14 221 patients, 9% had prescriptions with an average MEDD >= 90 mg. There were no significant changes in MEDD after EMR CDS implementation. Increasing age, Charlson Comorbidity Index score, female sex, black non-Hispanic race, non-opioid pain medication co-prescriptions, and specialty referrals were associated with a lower odds of MEDD >= 90 (high-dose threshold). Medicare or self-pay, substance abuse history, and pain agreements were associated with increased odds of prescribing above this high-dose threshold. After incorporation of EMR CDS, patients had higher rates of urine drug screens (17% vs 7%) and naloxone prescriptions (3% vs 1%, all P < .001). In addition, specialty referrals to physical or occupational therapy, orthopedics, neurology, and psychiatry or psychology increased in the postintervention period. Although emergency department use decreased (rate ratio 0.92; 95% confidence interval 0.89-0.95), hospitalization rates did not change.; Conclusions: EMR CDS improved adherence to opioid risk mitigation strategies. Further research examining which practice redesign interventions effectively reduce high-dose opioid prescribing is needed.