Abstract: Over the past several years, Medical Examiners in Kentucky and around the nation have observed a dramatic rise in drug intoxication deaths involving the prescription medication methadone. This documented rise in methadone-related deaths requires a better understanding of methadone’s pathophysiology and the ways it contributes to significantly increase morbidity and mortality. This study reviews 176 fatalities ascribed to methadone toxicity by the Office of the Chief Medical Examiner in Kentucky between 2000 and 2004. Postmortem toxicological analysis recorded a more than 10-fold increase in methadone toxicity fatalities, rising from 6 cases in 2000 to 68 cases in 2003. Of the 176 methadone-related fatalities, methadone was the only drug detected in postmortem blood and urine toxicological analyses in 11 (6.25%) cases. The mean methadone blood concentration of all 176 cases was 0.535 mg / L (0.02–4.0). The following psychoactive medications were detected: antidepressants (39.8%), benzodiazepines (32.4%), and other opioids in addition to methadone (27.8%). Cannabinoids were detected in 44 (28.4%) cases and cocaine or metabolite in 34 (21.9%) cases. Of the 95 cases with a known history of methadone use, 46 (48.4%) involved prescription by private physician. The interpretation of blood methadone concentrations alone or combined with other psychoactive drugs requires consideration of the subject’s potential chronic use of and tolerance to the drug. A thorough investigation into the practices of procurement and use/abuse of methadone is essential to arrive at the proper designation of the cause of death.