We conducted a randomized, unblinded, prospective study designed to determine the efficacy of single-dose azithromycin for the treatment of chancroid. Men and women 16 years of age and older who had darkfield-negative genital ulcers that were clinically suspected to be caused by Haemophilus ducreyi and who attended urban sexually transmitted disease clinics or presented to hospital emergency departments were enrolled in the study. Patients were randomized to receive 250 mg of ceftriaxone im or 1 g of azithromycin orally, both given as a single dose. They were followed for up to 23 days after treatment. For 65 patients, cultures were positive for H. ducreyi; there were 68 patients whose cultures were negative for both H. ducreyi and herpes simplex virus and who had no evidence of syphilis. All 133 patients returned for at least one follow-up visit. At the time of the last follow-up visit, all 32 patients whose cultures were positive for H. ducreyi and who were treated with azithromycin were clinically cured. In all 33 culture-positive cases in which ceftriaxone was used, there was either clinical improvement or cure at the time of the patient's last follow-up visit. In addition, azithromycin and ceftriaxone were equally effective in healing ulcers for which cultures were negative. We conclude that a single 1-g oral dose of azithromycin is as effective as a 250-mg im dose of ceftriaxone for the treatment of chancroid.