Aims Several addictovigilance studies have described the off‐label use of morphine sulfate (MS) for nonchronic pain in opioid use disorder (OUD) patients as an alternative to conventional opioid substitution treatments (OSTs). This study primarily sought to compare the incidence of unintentional opioid‐related overdose in the year following the prescription initiation in off‐label MS users, compared to OST‐maintained patients. Methods Sequential cohorts of OUD patients who were regularly dispensed MS, buprenorphine, or methadone, between 1 April 2012 and 31 December 2014, were retrospectively identified using the French nationwide healthcare data system. The incidence of overdoses, deaths, doctor shopping, and complications of a viral, bacterial or thrombotic nature, was compared using the Cox regression method. Results Overall, 1075, 20 834 and 9778 OUD patients without chronic‐pain were included in the MS, buprenorphine, and methadone cohorts, respectively. Overdose incidence was 3.8 ( P < .01 [95% confidence interval (CI): 2.1–6.8]) and 2.0 ( P = .02 [95%CI: 1.1–3.6]) higher in the MS cohort vs buprenorphine and methadone, respectively. Death incidence was 9.1 ( P < .01 [95%CI: 3.2–25.9]) and 3.9 ( P < .01 [95%CI: 1.4–10.7]) higher in the MS cohort vs buprenorphine and methadone, respectively. The incidences of other associated risks were significantly higher in the MS group vs OSTs, except for hepatitis C viral infection and thrombotic complications. Conclusion This first French comprehensive nationwide study reveals increasing overdose, death, bacterial infection, abuse and diversion risks when off‐label MS is initiated as alternative to OST. These results question the relevance of prescribing MS as a safe opioid maintenance treatment, considering its health risk profile.