Background and aims: Naltrexone is an opioid antagonist used as a maintenance drug for the treatment of opioid dependence and in opioid withdrawal regimens. The current study aimed to: (1) determine the clinical characteristics and circumstances of death of people undergoing naltrexone treatment for opioid dependence; and (2) determine the blood toxicology of cases including naltrexone concentrations, the presence of other drugs and a comparison of morphine concentrations in the presence and absence of naltrexone. Design: Retrospective study of all deaths among people undergoing naltrexone treatment for opioid dependence retrieved from the National Coronial Information System, 2000–17. Setting: Australia-wide. Cases: Seventy-four cases, with a mean age of 32.5 years; 81.1% male. Measurements: Information was collected on demographics, manner of death, naltrexone treatment history, toxicology and major organ pathology. Findings: Death was attributed to opioid toxicity in 86.5% of cases: accidental (79.7%), deliberate (6.8%). In 55.4% of all cases the decedent was maintained on oral naltrexone and 32.4% had a recent naltrexone implant. In five cases the decedent was undergoing opioid detoxification. Among those screened for naltrexone, naltrexone was present in the blood or urine of 52.5% (15.8% of oral maintenance cases, 85.7% of implant cases). Fourteen cases were known to have died from opioid toxicity with naltrexone present in their blood or urine. The median blood naltrexone concentrations were within the reported therapeutic range. Conclusions: The primary cause of death among people undergoing naltrexone treatment for opioid dependence in Australia from 2000 to 2017 was opioid toxicity, the majority of cases having been maintained on oral naltrexone. Cases in which naltrexone was not detected indicate the importance of treatment compliance. Deaths due to opioid toxicity where naltrexone was present indicates the possibility of overdose while naltrexone medication is maintained.