Alcohol and drug use have been associated with increased mortality and morbidity from thermal injury. To determine whether substance users (SUs) differed from controls, 398 burn patients were studied, of whom, 161 had a positive drug screen for either ethanol, cannabinoids, cocaine metabolites, amphetamines, phencyclidine, or benzodiazepines. SUs versus controls showed no difference in age, but had a significantly greater percentage of total burn surface area (TBSA) (25 vs. 17%), inhalation injury (29 vs. 7%), and mortality (14 vs. 3%). The alcohol users (AUs) and drug users (DUs) were similar in relation to sex, age, inhalation injury, percentage of TBSA, and type of burn. DU patients experienced the same increase in inhalation injury as the AU group compared to controls. The mortality of AU patients was twice that of DU patients and six times that of controls. The best independent predictors of death were age, inhalation injury, percentage of TBSA (p < 0.001), and ethanol use (p < 0.02).