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Patients with erythema migrans can fail to respond to antibiotic therapy. Persistent or recurrent erythema migrans, major sequelae such as meningitis and arthritis, survival of Borrelia burgdorferi and significant and persistent increase of antibody titres against B. burgdorferi after antibiotic therapy are strong indications of a treatment failure. Most, if not all, antibiotics used so far have been associated with a treatment failure in patients with erythema migrans. Roxithromycin and erythromycin are definitely or probably ineffective. However, doxycycline, amoxicillin, cefuroxime, ceftriaxone, azithromycin and high-dose penicillin V perform comparably well.