This case highlights a fatal drug-drug interaction between hydrocodone and diphenhydramine. The estimated total body burden of hydrocodone was 6- to 12-fold higher than acetaminophen, which is unexpected, as these two drugs were administered as a single formulation and have similar half-lives. Furthermore, hydromorphone was undetectable. Taken together, these findings are highly suggestive of a fatal opioid overdose precipitated by diphenhydramine.