Arthritis and carditis were mildly improved upon adoptive transfer of T cell enriched lymphocyte populations from Borrelia burgdorferi-infected (B. burgdorferi) (immune) compared with naive immunocompetent mice into B. burgdorferi-infected, severe combined immunodeficient (SCID) mice. Despite the relative purity of T cells in transferred cells, recipient mice seroconverted to B. burgdorferi. Thus, the effect could not be attributed to T cells alone. Passive transfer of serum from actively infected immunocompetent mice (immune serum) to SCID mice at the time of or before B. burgdorferi inoculation, or on Days 4, 8, and 12 after inoculation prevented or cured (respectively) infection and disease when examined at 15 days. Transfer of immune serum on Days 12, 16, 20, 24, and 28 did not clear infection at Day 30 but resulted in resolution of arthritis, indicating that immune serum can cause resolution of joint disease. Immune serum treatment could maintain arthritis resolution for up to 60 days. Immune serum from mice infected for 90 days or 15 months both had strong protective, post-infection, and arthritis-modulating activity, whereas hyperimmune serum to heat-killed B. burgdorferi or recombinant outer surface protein (Osp) A protected mice against infection when given on Day 0--but not at later intervals--and did not modulate disease. Immune serum from 90-day infected mice labeled spirochetes in joint tissues of SCID mice by immunohistochemistry, but hyperimmune serum to heat-killed B. burgdorferi or OspA did not. These studies suggest that the biologically active properties of immune serum may be directed toward yet to be defined, in vivo-expressed antigens of B. burgdorferi.