The efficacy of bicozamycin, a poorly absorbable antibiotic, in the treatment of acute diarrhea was assessed in a prospective, double-blind study of 140 adults from the United States visiting Guadalajara, Mexico. Patients randomly received bicozamycin (500 mg orally four times daily) or placebo for 3 days. The mean duration of illness was shorter in the bicozamycin than the placebo treatment groups for patients with diarrhea due to Shigella (37 versus 96 hours; p = 0.01), toxigenic Escherichia coli (31 versus 60 hours; p = 0.003), and unknown pathogens (18 versus 41 hours; p = 0.02). Cramps were significantly relieved by bicozamycin in all patients. Treatment failed in significantly fewer patients treated with bicozamycin than those treated with placebo when diarrhea was associated with Shigella, Salmonella or toxigenic E. coli. Bicozamycin was well tolerated and appears to be effective therapy for acute travelers' diarrhea of diverse causes. These data show the value of an antibiotic in the therapy of toxigenic E. coli infection and indicate a need to reevaluate the clinical dictum that nonabsorbable antibiotics are ineffective against invasive enteropathogens.