AbstractCompound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD). Our previous work demonstrated no relationship between pre-treatment CACC and ORT buprenorphine doses; we hypothesised that CYP2D6 activity would partially account for this disconnection. One hundred six participants with CUD were compared to a published population sample of 5408 Australian patients. Mean age of participants with CUD at treatment entry was 35 years, with mean 6.1 years duration of CUD. Mean codeine dose was 660 mg/day (range 40–2700 mg). Mean calculated CYP2D6 activity scores were significantly higher in the codeine group (CUD 1.65 + 0.63 vs. Gen pop 1.39 + 0.65, Wilcoxon W = 347,001, p < 0.001). Pre-treatment CACC dose weakly predicted sublingual buprenorphine doses overall; there was a stronger relationship within ultrarapid metabolisers. While normal and ultrarapid metabolisers of codeine were more likely to have a diagnosis of CUD, poor or intermediate CYP2D6 metaboliser status may protect against CUD.