Three clinical trials were carried out to examine the efficacy of various antimicrobial agents in the treatment of travelers' diarrhea among students from the United States in Mexico. Thirty-seven subjects received twice daily for five days 160 mg of trimethoprim (TMP) and 800 mg of sulfamethoxazole (SMZ), 38 received 200 mg of TMP, and 35 received a placebo. Another group of students were given 100 mg of furazolidone (47 students) or ampicillin (47 students) four times a day for five days. In the third study, 500 mg of bicozamycin (72 students) or a placebo (68 students) was given four times a day for three days. Most students who received TMP-SMZ (78%), TMP (84%), or bicozamycin (85%) had recovered by 48 hr after initiation of treatment, as compared with 14% and 47% in the corresponding placebo groups and 55% in the furazolidone group. The agents had a positive effect for all etiologic categories, including diarrhea due to enterotoxigenic Escherichia coli and Shigella strains and illness without any established etiologic agents. Treatment failures were unusual with TMP-SMZ, TMP, and bicozamycin therapy (5% vs. 39% for the placebo-treated students). The drugs were well tolerated. The use of TMP-SMZ or TMP alone in the empiric treatment of moderate to severe travelers' diarrhea is advocated.