Azithromycin, doxycycline and phenoxymethylpenicillin were compared in a prospective, randomized study of 64 patients with typical erythema migrans. Twenty patients were treated with oral azithromycin, 250 mg bd for two days followed by 250 mg od for eight days, 21 patients were given phenoxymethylpenicillin 1 million IU tds for 14 days and 23 patients received doxycycline, 100 mg bd for 14 days. All patients were followed up for 24 months. There were no significant differences between the groups with respect to the persistence of cutaneous lesions after starting treatment; the mean durations were 10.5 days in the penicillin group, 8.8 days in the doxycycline group and 8.6 days in the azithromycin group. There were statistically significant differences in terms of the resolution of associated local and/or systemic symptoms. The response time was shortest in patients treated with azithromycin. Two patients who received phenoxymethylpenicillin and two given doxycycline subsequently developed major manifestations of Lyme borreliosis; these did not occur in patients receiving azithromycin. Although azithromycin has been shown to be effective in the treatment of erythema migrans, further studies will be needed to determine the optimal dosage and duration of therapy.