The efficacy and safety of intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) were evaluated in 22 adults with serious infections caused by gram-negative bacteria. These infections included pneumonia, meningitis, pyelonephritis, deep-seated abscesses, and endocarditis. Of the 19 patients who could be evaluated, 12 (63%) were cured, and four (21%) showed definite improvement; three patients (16%) failed to respond to treatment. The only serious side effect occurred in a patient who had an acute reaction after his first dose. Mild adverse reactions were relatively common: three patients (13.6%) developed skin rashes, in one case with bronchospasm and eosinophilia. Mild transient decline of renal function was observed in five patients (22.7%) and decline of hepatic function in seven patients (31.8%); these abnormalities were not necessarily attributable to the drug. Although side effects were more common than previous reports indicate, intravenous TMP-SMZ was effective in the treatment of life-threatening infections unresponsive to other antibiotics.