Transfer of immune serum from immunocompetent mice infected with B. burgdorferi protects mice against syringe challenge, and transfer of immune serum after infection is established induces arthritis resolution but does not clear infection or spirochetemia or resolve carditis. Immune serum had very-high-titer passive protective activity against syringe challenge but failed to protect mice against host-adapted spirochetes when they were challenged with infected tissue transplants. Mice were passively immunized at selected intervals relative to challenge inoculation with antisera to recombinant forms of an immunodominant region of flagellin, P39, and OspC (which are recognized by immune serum), but none provided protection or modified existing infection or disease. Results suggest that spirochetes within joints, but not in other tissues, are selectively vulnerable to immune serum and that immune serum appears to contain antibody against yet-to-be-identified antigens that may be selectively expressed in the context of joint tissue.