In a randomized multicenter therapeutic trial, 32 patients with erythema migrans received oral azithromycin 500 mg once daily and 33 patients received phenoxymethylpenicillin (penicillin V) 1 million U three times daily for 10 days. Follow-up was for a median of 17 (range 3-32) months. Four weeks after initiation of therapy, 20 (62%) patients given azithromycin and 17 (51%) patients given penicillin V were completely free of all signs and symptoms and did not develop new ones subsequently (no significant difference). Three months after initiation of therapy, the corresponding figures were 25 (78%) azithromycin and 28 (85%) penicillin V recipients (no significant difference). There were only minor sequelae such as arthralgia, headache, fatigue, stiff neck and dysesthesia. Azithromycin led to a significantly faster resolution of the erythema migrans than penicillin V (p < 0.001). Significantly more patients with more severe compared with mild initial disease had an elevated IgM antibody titer prior to therapy (p < 0.001). Usually mild to moderate side effects occurred in 12 patients given azithromycin and five patients given penicillin V (p < 0.05). Azithromycin appears to be as effective as penicillin V for the treatment of early Lyme borreliosis and it seems to clear the erythema migrans more promptly.