Lyme borreliosis in transgenic mice tolerant to Borrelia burgdorferi outer surface protein A (OspA) from the weakly virulent B. burgdorferi 25015 was assessed because the response to OspA has been implicated in protective immunity and is suspected in disease pathogenesis. B. burgdorferi 25015 is infectious but does not cause significant arthritis in C3H/HeN mice. Tolerance of mice to B. burgdorferi N40 OspA had no effect on disease. Since B. burgdorferi N40 is more virulent than and genetically distinct from B. burgdorferi 25015, the generality of these findings was investigated. OspA-25015-transgenic mice were tolerant to OspA-25015 and did not develop OspA antibodies or cellular responses following immunization with OspA-25015. The development and resolution of Lyme arthritis was similar in transgenic and nontransgenic littermates, suggesting that ablation of the OspA-25015 response does not cause B. burgdorferi 25015 to become more arthritogenic.