To identify factors contributing to methadone-related deaths in Ontario in 2004, demographic factors, methadone blood levels, evidence of concurrent drug use, the source of methadone (prescribed or illicit), and its contribution in exacerbating preexistent disease were studied to identify users at risk for methadone toxicity and death. This retrospective study reviewed postmortem data, autopsy reports, police reports, hospital data, and postmortem toxicological analyses available in the Ontario Chief Coroner's Information System. There were 54 cases with methadone detected in postmortem blood samples. Of total, 9 cases were not included in the study because of incomplete documentation. About 11 deaths were due to methadone toxicity alone; 25 deaths were due to combined methadone and other drug toxicity (notably cocaine and alcohol); 7 deaths were due to the exacerbation of a preexisting disease by methadone; 1 death was due to disease alone, and 1 death was due to trauma sustained in a motor vehicle collision. A significant number of methadone-related deaths were due to illicit methadone ingestion, which exceeded the opioid tolerance level. The source of methadone in these cases was unknown. Drug addicts, unaware of the hazard of consuming other illicit or prescription drugs concurrently, are at risk. This study demonstrated that methadone toxicity is enhanced by underlying disease, especially in individuals with underlying cardiac and pulmonary pathology.