The symptoms of Lyme borreliosis are similar to those of a variety of autoimmune musculoskeletal diseases. Persistence of complaints is frequently interpreted as unsuccessful antibiotic treatment of Borrelia-associated infections. However, such refractory cases are rare, and re-evaluation of differential diagnoses helps to avoid the substantial risk of long-term antibiotic therapy. In this study, we analyzed patients who presented to our rheumatology unit with previous suspected or diagnosed Lyme borreliosis. Eighty-six patients from a 3.5-year period were evaluated. The mean age of patients was 49.2 +/- 17.2 years; 60% (n = 52) reported a tick bite and 33% (n = 28) an erythema. Forty-seven percent (n = 39) had positive enzyme-linked immunoassay results and Western blots (Mikrogen, Martinsried, Germany). All but 12 patients had already received antibiotic treatment previously. Nine percent (n = 8) had ongoing or recent Lyme borreliosis. Twenty-nine percent (n = 25) showed clinical symptoms and radiographic changes compatible with degenerative disorders of the cervical and/or lumbar spine. These patients were significantly older when compared to the other patients (59.3 +/- 13.7 years vs 46.1 +/- 17.2 years, p = 0.001). Seventeen percent (n = 16) had arthropathies related to psoriasis or rheumatoid arthritis. Twelve percent (n = 10) were positive for the HLA B27 antigen. Other diseases were less frequent. Six patients (7%) could not be diagnosed conclusively, and four of these patients had negative Borrelia immunoassay results. In conclusion, Borrelia-associated diseases were rare in this study. Differential diagnoses helped to initiate a successful disease-specific therapeutic strategy.