Azithromycin was shown to be as effective as standard benzathine penicillin and erythromycin in the therapy of active syphilis in the rabbit model. Following production of primary chancres by intradermal inoculation of 10(6) Treponema pallidum, groups of six rabbits were treated with benzathine penicillin (200,000 units im weekly for two weeks), erythromycin base (30 mg/kg/day orally four times daily for 15 days) or azithromycin (30 mg/kg/day given orally once or twice daily for 15 days); one group was untreated. Daily darkfield (DF) microscopic examinations of chancre aspirates were conducted to identify motile organisms. Although all treated animals became DF negative prior to completion of therapy, the median time to DF negativity was longer in animals given azithromycin once daily, compared with animals receiving benzathine penicillin (P less than 0.01); no difference was seen in comparison with animals receiving erythromycin. Untreated animals remained DF positive for greater than 15 days. The mean maximum lesion diameters for all treated animals were similar and were significantly smaller than in untreated rabbits; fewer lesions ulcerated in treated than in untreated animals. Subsequent dose-ranging studies indicated that administration of lower doses of azithromycin (15 mg/kg/day given orally either once or twice daily, or 7.5 mg/kg/day given once daily) was as effective as benzathine penicillin for therapy of active syphilis in this model, though the median time to darkfield negativity was significantly longer in the azithromycin-treated animals (P less than 0.01). Persistent infection was demonstrable in lymph nodes of untreated animals, but no evidence of virulent T. pallidum was found three months following transfer of tissue from any animal treated with penicillin, erythromycin, or azithromycin.