Stress ulcer prophylaxis is a routine aspect of the care of critically injured patients. Recent reports have suggested that patients undergoing prophylaxis with histamine antagonists are predisposed to nosocomial pneumonia, and that treatment with sucralfate can prevent this problem. An open, prospective randomized trial of three regimens was conducted with 278 evaluable patients. The patients were assigned to one of three group: the group receiving sucralfate, the group receiving a cimetidine hydrochloride bolus, and the group undergoing continuous infusion with cimetidine. Stress ulceration developed in 8% of patients in the sucralfate group, 13% of patients in the cimetidine bolus group, and 12% of patients in the cimetidine infusion group, while nosocomial pneumonia developed in 29% of patients in the sucralfate group, 32% of patients in the cimetidine bolus group, and 23% of patients in the cimetidine infusion group. Multivariate analysis of risk factors associated with pneumonia demonstrated independent significance for score on the Glasgow Coma Scale, Injury Severity Score, cord injury, shock, and head injury. Only spinal cord injury was associated with stress ulceration. We conclude that sucralfate and cimetidine are both effective for stress ulcer prophylaxis and that there is no association of cimetidine with nosocomial pneumonia.