OBJECTIVE: To evaluate the efficacy, safety, and cost of using cimetidine, famotidine, and lansoprazole for stress ulcer prophylaxis (SUP) at our institution and determine which agent was most cost-effective. METHODS: An observational study of adults admitted to the medical, surgical, or cardiovascular intensive care unit was conducted to compare the cost and effectiveness of cimetidine, famotidine, and lansoprazole for SUP. Patients were identified for inclusion during three 2-week periods in 2000. Medical record reviews were conducted to gather data regarding the costs associated with the administration of SUP drugs and the treatment of any adverse events or therapeutic failures. Decision analysis was used to determine the average cost per patient for each treatment arm. A cost-effectiveness analysis was then conducted to determine which of the SUP agents was associated with the least cost without adversely affecting patient outcomes. A sensitivity analysis was applied to determine the robustness of the data. RESULTS: Eighty-eight patients were included in the analysis. Five of the patients started on cimetidine experienced therapeutic failure, whereas no patients receiving lansoprazole experienced therapeutic failure. For these reasons, and because lansoprazole is an oral agent, the average costs associated with lansoprazole use were lower than with the use of cimetidine. Lansoprazole was found to be the most cost-effective therapy. CONCLUSIONS: This study showed that lansoprazole is a cost-effective agent for the use of SUP at our institution. However, due to the higher cost of intravenous pantoprazole, the model demonstrates that, assuming equal effectiveness, intravenous pantoprazole would not be cost-effective when compared with cimetidine.