BACKGROUND AND OBJECTIVES: Azithromycin is a new, long-acting azalide antibiotic that is active against Neisseria gonorrhoeae. A single oral dose of 1.0 g is effective against uncomplicated genital infection with Chlamydia trachomatis. GOAL OF THIS STUDY: To compare the efficacy and tolerance of single-dose treatment of uncomplicated gonorrhea with azithromycin, 2.0 g orally, and ceftriaxone, 250 mg intramuscularly. STUDY DESIGN: Seven hundred twenty-four men and women with presumptive, uncomplicated gonorrhea were treated with azithromycin 2.0 g orally or ceftriaxone 250 mg intramuscularly in a 2:1 ratio in a multicenter, open, randomized control trial in 10 public sexually transmitted disease clinics in the United States. Patients were followed up in 5 to 9 days and, for a subset of patients, 12 to 18 days after treatment. The main outcome measures were the isolation of N. gonorrhoeae and C. trachomatis and patient-reported side effects. RESULTS: Among infected patients who returned for follow-up, N. gonorrhoeae was eradicated from all anatomic sites in 370 of 374 (98.9%; 95% confidence interval [95%CI] 97.9%-100%) treated with azithromycin and 171 of 175 (97.7%; 95%CI 95.5%-99.9%) given ceftriaxone. Treatment with either drug was effective in all 73 patients infected with beta-lactamase-producing N. gonorrhoeae. Chlamydial infection was eradicated in all 17 patients given azithromycin who returned and were recultured at follow-up and in two of seven patients given ceftriaxone (P < 0.001). Gastrointestinal side effects occurred in 35.3% (95%CI 30.7%-39.8%) of patients given azithromycin; of those with symptoms, these were moderate in 10.1% and severe in 2.9%. CONCLUSIONS: Azithromycin 2.0 g and ceftriaxone 250 mg are equally effective in the treatment of uncomplicated gonorrhea. Azithromycin was associated with a relatively high frequency of gastrointestinal side effects and is expensive, but it has the advantages of oral administration and efficacy against concomitant chlamydial infection.