Background: Preventive therapy is an important element of syphilis control efforts. No currently recommended, single-dose alternatives to penicillin G benzathine are available for treatment of incubating syphilis. Objective: To evaluate the use of a single 1.0-g dose of azithromycin for treatment of persons recently exposed to sexual partners with infectious syphilis. Design: Single-center, open-label, randomized pilot study to compare azithromycin with penicillin G benzathine therapy. Participants were evaluated serologically for 3 months. Setting: Sexually transmitted disease clinic in Birmingham, Alabama. Participants: 96 participants who in the preceding 30 days had been exposed to partners with infectious syphilis through sexual intercourse. Measurements: Syphilis prevention, as indicated by nonreactive serologic tests (rapid plasma reagin and fluorescent treponemal antibody-absorbed), throughout the 3-month follow-up. Results: Among 96 participants enrolled, none of 40 evaluable persons in the azithromycin group and none of 23 evaluable persons in the penicillin group developed evidence of syphilis. Significantly more penicillin-treated participants (21 of 44 [48%]) than azithromycin-treated participants (12 of 52 [23%]) became nonevaluable during follow-up (P = 0.01). Conclusion: A single 1.0-g dose of azithromycin seems to be efficacious for prevention of syphilis in persons exposed to infected sexual partners.