CONTEXT: Forensic pathologists regularly investigate the deaths of individuals with a history of drug abuse. Autopsy, including toxicology testing, reveals no cause for death in a subset of this cohort. OBJECTIVE: To determine whether deaths with an undetermined cause and manner of death are associated with a history of drug abuse. DESIGN: Retrospective matched case-control study of 52 decedents whose cause of death remained undetermined following autopsy, matched 1:2 to a control group of living patients admitted for cholecystectomy according to age and date of death or procedure. RESULTS: Individuals whose cause of death was undetermined were 5.3 times (95% confidence interval, 1.9-14.5) more likely to have a history of drug abuse than were patients with cholecystitis. CONCLUSIONS: Decedents with a history of chronic drug abuse appear to be at an increased risk of dying by their chronic drug abuse, even in the absence of any anatomical or toxicologic finding at autopsy to account for death.