BACKGROUND Patients with severe burns are at increased risk of developing methicillin-resistant Staphylococcus aureus (MRSA) ventilator-associated pneumonia. This study was designed to determine whether MRSA pneumonia can be prevented by prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX). METHODS We conducted a prospective, randomized, placebo-controlled study in patients with severe burns (> or = 20%), who required ventilator support. Prophylaxis was done with oral TMP-SMX (80 mg/400 mg) three times daily for 10 days from 4 to 6 days after burn injury. The incidence of MRSA pneumonia and the side effects were evaluated during the administration period. RESULTS Twenty-one patients were assigned to receive TMP-SMX, and 19 patients to receive placebo. The incidence of MRSA pneumonia was 4.8% in the TMP-SMX group and 36.8% in the placebo group, showing a significant difference (p = 0.017). No major side effects of therapy were seen in the TMP-SMX group. CONCLUSIONS Prophylactic treatment with TMP-SMX can prevent MRSA pneumonia in severely burned patients.