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Objective To compare the pattern of antibody responses to Borrelia burgdorferi in patients with antibiotic-refractory, antibiotic-responsive, or non–antibiotic-treated Lyme arthritis as an indirect measure of spirochetal persistence or eradication. Methods At least 3 serial serum samples from 41 patients with antibiotic-refractory arthritis and 23 patients with antibiotic-responsive arthritis, and samples from 10 non–antibiotic-treated, historical control patients were tested for IgG reactivity with B burgdorferi sonicate and 4 differentially expressed outer surface lipoproteins of the spirochete, by enzyme-linked immunosorbent assay. Results Among non–antibiotic-treated patients, antibody titers to B burgdorferi antigens remained high throughout a 2–5-year period of arthritis. In contrast, in patients with antibiotic-responsive arthritis, in whom joint swelling usually resolved during a 1-month course of oral antibiotic therapy, the median antibody titers to most of the spirochetal antigens remained steady or decreased during the first 1–3 months after starting antibiotic therapy. In patients with antibiotic-refractory arthritis, who had persistent joint swelling for a median duration of 10 months despite 2–3 months of oral or intravenous antibiotics, the median titers to most antigens increased slightly during the first 1–3 months. However, by 4–6 months after starting antibiotic therapy, reactivity with all antigens declined similarly in both antibiotic-treated groups. Conclusion Whereas the antibody titers to B burgdorferi remained high in non–antibiotic-treated patients, the titers declined similarly 4–6 months after starting therapy in patients with antibiotic-responsive or antibiotic-refractory arthritis, suggesting that synovial inflammation persisted in patients with antibiotic-refractory arthritis after the period of infection.