The host response to Borrelia burgdorferi is likely to play a role in the pathogenesis of Lyme arthritis. Whereas most patients with Lyme arthritis can be cured with antibiotic therapy, approximately 10% of the patients have persistent arthritis for months or even several years after antibiotic treatment. In this study, we tested the hypothesis that the T cell response to one or more antigens of B. burgdorferi is different in patients with treatment-responsive or treatment-resistant Lyme arthritis. For this purpose, 313 B. burgdorferi-specific T cell lines were derived from the synovial fluid or peripheral blood of four patients with treatment-responsive Lyme arthritis and five patients with treatment-resistant arthritis. 87 T cell lines from treatment-responsive Lyme arthritis and 112 lines from the treatment-resistant group were examined for the recognition of five recombinant. B. burgdorferi proteins: outer surface proteins A (OspA), B, C, p39, and p93. In both groups of patients, the T cell lines frequently recognized OspB, and only occasionally recognized OspC, p39, and p93. In contrast, OspA was preferentially recognized by T cell lines from patients with treatment-resistant arthritis, but only rarely recognized by T cell lines from patients with treatment-responsive arthritis (odds ratio 28.4, 95% confidence interval 9.2-87.8, p < 0.005). These results are compatible with the hypothesis that the T cell response to B. burgdorferi OspA is involved in the pathogenesis of treatment-resistant Lyme arthritis.