When immunocompetent mice are inoculated with Borrelia burgdorferi, they develop acute arthritis and carditis that undergo spontaneous regression despite the persistence of infection. Specific T- and/or B-cell immunity appears to be necessary for resolution of disease manifestations. Humoral immune responses to B. burgdorferi are also important in prevention of B. burgdorferi infection, in that passive transfer of immune sera or protective monoclonal antibodies prevents the spirochete from establishing infection. It has previously been suggested that complement is necessary for effective antibody-mediated host responses against B. burgdorferi. To investigate the role of complement in the pathogenesis and prevention of Lyme disease, we compared the responses to B. burgdorferi challenge inoculation of mice genetically deficient in the fifth component of complement (C5) with those of C5-sufficient mice. All C5-deficient strains tested were susceptible to B. burgdorferi infection, and disease manifestations underwent regression in a similar time-course to those of complement-sufficient mice. Moreover, passive immunization of C5-deficient mice with either immune rabbit sera or neutralizing monoclonal antibody protected them from challenge infection. These results demonstrate that the expression of Lyme disease is not altered in mice deficient in C5 and that C5-mediated complement activation is not necessary for antibody-mediated protection from infection.