Increases in methadone and oxycodone related deaths have been recently documented in the United States. In response to these reports, the authors investigated cases over a six-year period in which postmortem toxicological analyses revealed the presence of methadone, hydrocodone, and oxycodone. The study was designed to determine whether regional methadone-associated mortality in Cuyahoga County reflected national trends and more specifically, to distinguish methadone mortality from other commonly used opioid analgesics. All records of decedents that were found to be positive for methadone, hydrocodone, and/or oxycodone in 1998-2003 were reviewed. The cause and manner of death and demographic information was compiled. The cases were divided into lethal intoxications and cases where a positive result was determined to be an incidental finding. Lethal intoxications as a result of only methadone, hydrocodone, or oxycodone were separated from polydrug intoxications. Thoroughout the study, an increase was observed in the number of positive cases. In contrast to recent national data, although the number of methadone-positive cases increased from 4 in 1998 to 18 in 2003, this did not result in an increase in methadone overdoses [1 death in 1998 (25%) to 4 deaths in 2003 (22%)]. Although the pharmacokinetic profiles differ, methadone, hydrocodone, and oxycodone lethal intoxications equally comprised 28-29% of cases in which these drugs were detected. There was an overlap in the range of blood concentrations observed for the drug-related death groups and the incidental finding groups. However, mean and median concentrations in oxycodone and hydrocodone related deaths were more than two times greater than those in non-drug-related deaths.