The use of antibacterial drugs was first shown to effectively reduce the occurrence of traveler's diarrhea nearly 50 years ago. The approach was not encouraged for general use by a Consensus Development Conference in 1985 because of concerns about adverse effects of the drugs and the possible development of resistance against systemically absorbed drugs. When therapy with poorly absorbed rifaximin was shown to be as effective as therapy with systemically absorbed drugs in shortening the duration of traveler's diarrhea, without the development of resistant coliform flora, the use of rifaximin for the prevention of traveler's diarrhea was studied. In the present study, rifaximin provided 72% protection against the development of diarrhea and 77% protection against active or treated diarrhea during 2 weeks of drug administration to United States students in Mexico. Rifaximin offers a potentially useful approach for preventing traveler's diarrhea. Potential areas of future study include use of the drug to prevent diarrhea due to mucosally invasive bacteria, including ciprofloxacin-resistant Campylobacter species, and to reduce the occurrence of postinfectious irritable bowel syndrome.