Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).