We have investigated the specific humoral immune response and its correlation to the development of disease after experimental inoculation of B, burgdorferi in different inbred strains of mice. All mouse strains tested showed high levels of specific IgM antibodies during the initial 10 days of infection. Specific IgG antibodies predominantly of the IgG_2a, IgG_2b and IgG₃ isotypes were found in increasing amounts by 14 days post infection. Antibody titers peaked at days 65 and 110. Particularly low titers of specific IgM and/or IgG antibodies were detected in sera of AKR/N and B10.BR mice. Antibodies specific for numerous B. burgdorferi antigens including the outer surface proteins A (31 kDa) and B (34 kDa) and a protein(s) of molecular mass of ∼40 kDa, most probably 41 kDa (flagellin) and/or 39 kDa (p39), were induced in all inbred mouse strains within 2 weeks inoculation albeit in varying concentrations. Later during infection, the patterns of antibody specificities were much more complex. With regard to development of disease all strains of mice tested fall into three groups: (a) mice of H‐2^k haplotype (AKR/N, C3H/HeJ, C3H/HeN, B10.BR) developed a chronic progressive arthritis in the tibiotarsal joints, (b) mice of H‐2 haplotypes, H‐2^b (C57BL/6), H‐2^j (B10.WB), H‐2^r (B10.R111) and H‐2^s (B10.S) developed arthritis of variable duration and intensity which was not progressive and (c) mice of H‐2^d haplotype (BALB/c, DBA/2, C.B‐17, B10.D2, Cal.20), irrespective of their background genes or Igh allotype, showed no clinical signs of arthritis at any time point following inoculation of B. burgdorferi organisms. The finding of similar patterns of apparently protective antibodies in all mouse strains tested together with the striking association between the H‐2^d haplotype and resistance, and between the H‐2^k haplotype and the occurence of B. burgdorferi‐induced e arthritis suggest a critical role of T cells in the development of the disease in mice.