Antibiotic treatment has been proven to be effective in about 90% of patients with Lyme arthritis in controlled studies. Overt arthritis persisting in spite of antibiotic therapy is rare and most likely has an autoimmune background. More frequently, patients with history of Lyme borreliosis present with non-specific articular and musculosceletal symptoms, which seem to be permanent sequelae of arthritis or constitute part of so called post-Lyme disease syndrome, of unclear pathogenesis. As persistence of active infection after proper antibiotic therapy is unlikely, repeated treatment seems of no benefit in most of the patients. No more than 2-3 attempts of antibiotic therapy should be undertaken; if symptoms persist, symptomatic and anti-inflammatory treatment should be introduced. Lack of response to antibiotics should also point to co-existing musculoskeletal morbidity or to improper diagnosis of Lyme borreliosis, which is frequent due to common occurrence of false-positive serologic tests results.