BACKGROUND: A randomized, multicenter, open clinical trial was undertaken in order to compare the efficacies of azithromycin and doxycycline in the treatment of patients with Lyme disease associated with erythema migrans. PATIENTS AND METHODS: A total of 48 patients was treated orally with azithromycin, 500 mg bid on the 1st day, followed by 500 mg once daily for the next 4 days or doxycycline (40 patients) 100 mg bid for 14 days. RESULTS: Intention-to-treat analysis of clinical efficacy showed no difference between the two treatment regimens. Clinical success was observed in 46 (95.8%) azithromycin- and 33 (82.5%) doxycycline-treated patients, (p = 0.0731). Minor symptoms persisted or appeared in the posttreatment period in two of 47 azithromycin- and three of 35 doxycycline-treated patients (p = 0.646). Major manifestations appeared only in two patients in the doxycycline group (p = 0.179). There was no difference in the tolerability of both drugs. CONCLUSION: Azithromycin (a total dose of 3 g) is equally effective as standard doxycycline treatment for erythema migrans in adult patients.