In a double-blind study of the treatment of disease caused by enterotoxigenic Escherichia coli (ETEC), diarrhea was induced in volunteers with a trimethoprim (TMP)- and sulfamethoxazole (SMZ)-susceptible strain of E. coli that produces both heat-stable and heat-labile toxin. III volunteers were then treated with TMP, TMP-SMZ, or placebo. Volunteers treated with both TMP alone and the TMP-SMZ combination showed a substantial decrease in the duration and severity of the illness, as compared with the placebo-treated controls. TMP-resistant (MIC, 3.1-12.5 micrograms/ml) ETEC were isolated from stool cultures of five of 10 TMP-treated volunteers and none of 10 TMP-SMZ-treated volunteers after 48 hr of therapy, and in two volunteers the appearance of resistant organisms was associated with a clinical relapse. These data suggest that the TMP-SMZ combination should be evaluated in field trials to determine its usefulness as an adjunct to replacement of fluid and electrolytes in the therapy of ETEC diarrhea.