We have compared the effectiveness of non-acid neutralizing stress ulcer prophylaxis (SUC) with sucralfate (n = 48) with that of acid neutralizing prophylaxis (AN) utilizing antacids and cimetidine (n = 48) in the prevention of stress ulcer bleeding and nosocomial pneumonia (PN) in thermally injured patients. In the subset of intubated patients, the incidence of PN was 17.8% and 42.8% in the AN and SUC groups, respectively (p < 0.05) despite a similar postburn time of onset of pneumonia. Ten patients in each group died. Three patients in the SUC group developed upper GI bleeding with one requiring gastrectomy. Bacterial colonization of the upper airway occurred in virtually all patients, whereas 83% (SUC) and 96% (AN) had colonization of gastric contents. Gram-negative colonization rates for the upper airway were not different (70%) whereas 48% of SUC patients compared with 60% of AN patients had gram-negative gastric colonization. In conclusion, SUC therapy was efficacious in the prevention of stress ulcer bleeding but did not alter the rate of bacterial colonization of the airway or gastric contents, and was associated with a higher incidence of nosocomial pneumonia in intubated patients.