To determine the etiology of the decreased efficacy of cimetidine in burned and critically ill surgical patients, we studied the kinetics and dynamics of the drug in eight burned patients at a mean of 12 days after the burn. The kinetics were compared with those of nine healthy controls. The elimination half-life of cimetidine in burned patients was significantly reduced (2.2 v 1.5 hours), and total clearance significantly increased (8.2 v 13.3 mL/min/kg). Creatinine and total cimetidine clearance were highly correlated with size of the burn. In the patients studied, 63% of the dose was excreted in eight hours, compared with 45% after 24 hours in controls. Gastric pH was maintained at 4 or higher as long as plasma levels of cimetidine were held above 0.5 microgram/mL. Thus, the increased clearance of cimetidine might explain the decreased effectiveness of this drug in burned and possibly other surgical patients. Dose schedules may need to be altered to compensate for the enhanced clearance of this drug.