Methadone, an orally active opioid agonist, is routinely used in the treatment of opiate addiction and in the management of chronic pain. Reports of death that have been attributed to methadone use are somewhat common, yet methadone continues to be widely available. Many researchers have noted the difficulties of interpreting postmortem methadone concentrations. Moreover, fatal methadone concentrations vary widely from person to person, particularly when methadone is used in combination with other drugs. The current study probed how the abuse of methadone contributed to the deaths of 139 methadone-related cases investigated by the Palm Beach Medical Examiner’s Office between 1998 and 2002. Of the 139 methadone-related cases, 23 were attributed to methadone toxicity alone while 75 were attributed to combined drug toxicity. The remaining cases included 7 in which methadone was considered incidental, 11 in which the deaths were natural, and 9 in which the deaths were due to trauma. Significant overlap between groups was observed in postmortem blood methadone concentrations. In cases in which the death was attributed to methadone toxicity alone, concentrations ranged from 0.114 mg/L to 1.939 mg/L. In cases of combined drug toxicity, concentrations ranged from 0.050 mg/L to 1.903 mg/L. When deaths were attributed to other drugs, methadone concentrations ranged from 0.069 mg/L to 0.644 mg/L; deaths attributed to natural causes had methadone concentrations of 0.062 mg/L to 1.090 mg/L; and deaths attributed to trauma had methadone concentrations of 0.072 mg/L to 2.7 mg/L. The findings indicate that definitive lethal blood methadone levels may not be established because of the wide range of lethal doses observed in the sample and because of the presence of other drugs. In order to determine the cause of death in methadone-positive cases, autopsy reports should be correlated with investigative findings. Table, references