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Background: The literature on results from primary care-based opioid-prescribing protocols is small and results have been mixed. To advance this field, we evaluated whether opioid prescribing changed after a comprehensive protocol was implemented and whether change was associated with the number and type of risk reduction tools adopted., Methods: Electronic medical record data were obtained for 2607 patients. Demographics, Patient Health Questionnaire-9 scores, body mass index, and utilization levels of protocol elements were measured for 24 months prior and 18 months post implementation of an opioid-prescribing protocol within a federally qualified health center. χ 2 and t -tests were computed to estimate change in opioid prescribing, morphine-equivalent dose, comedication prescribing, and number and type of protocol elements utilized., Results: The opioid protocol was associated with an increase in urine drug screens from 18.3% to 26.8% from pre to postimplementation ( P < .0001). There was no significant increase in opioid treatment agreements. Tramadol (21.4% to 16.8%, P = .0006) and antidepressant (56.0% to 51.6%, P = .012) prescribing significantly decreased. Total opioid prescriptions and maximum morphine-equivalent doses were similar from pre to postimplementation. Protocol elements were more often used when patients had a higher opioid dose and were receiving benzodiazepines., Conclusions: Implementing a multi-faceted opioid-prescribing protocol was not associated with change in number or dose of opioid prescriptions but was associated with greater use of urine drug screens, and risk reduction tools were used more often in high-risk patients. Implementation research is needed to identify barriers to maximizing adherence to opioid protocols., Competing Interests: Conflict of interest: none declared., (© Copyright 2020 by the American Board of Family Medicine.)