Increased drug resistance among enteropathogens is an emergent problem in travelers' diarrhea. This randomized, double-blind trial was conducted in Guadalajara, Mexico, during the summers of 1999-2001 to compare azithromycin with levofloxacin for the treatment of travelers' diarrhea. A total of 217 US adults were randomized to receive a single oral dose of azithromycin (1000 mg; 108 persons) or levofloxacin (500 mg; 109 persons), with a follow-up period of 4 days. Three patients in each group dropped out of the study. The median time between initiation of therapy and passage of the last unformed stool (azithromycin group, 22.3 h; levofloxacin group, 21.5 h) and the number of unformed stools passed during the 4-day follow-up period (azithromycin group, 6.5; levofloxacin group, 5.5) were similar. Treatment failure occurred in 10 patients (9.5%) receiving azithromycin and 8 patients (7.5%) receiving levofloxacin. Possible minor, self-limiting adverse events occurred in 57 patients in each treatment group. Azithromycin was found to be a safe and effective alternative to levofloxacin for the treatment of acute travelers' diarrhea in US adult travelers to Mexico.