The infrequent use of guinea pig in experimental syphilis, the not well genetically and immunologically characterized strains of animals originating from places with unspecified conditions of husbandry, and the various strains of Treponema pallidum used for infection provided inconsistent and discouraging results. For eight decades the rabbit has been the major animal model in studies of syphilis. However, the lack of readily available inbred strains of rabbits--necessary for adoptive transfer experiments--has been a stumbling block in revealing the mechanisms responsible for immunity, susceptibility, and resistance to T. pallidum infection. These difficulties have recently been overcome by demonstration of inbred strains susceptible to T. pallidum infection, paving the way to studies of adoptive immunity. The guinea pig may also be a better model than the rabbit for immunomanipulations (irradiation, injection with antibodies specific to various cell populations), allowing a closer insight into the immunopathologic mechanism operating during the course of syphilitic infection. The "rediscovery" of the guinea pig as a model for experimental syphilis and recent years of intensive studies justify a review summarizing older data and providing the most recent information. The authors, having first-hand experience with this model, will provide detailed information on (1) historical background; (2) course of infection with T. pallidum in inbred and outbred strains of guinea pigs; (3) the ID50 for various strains; (4) various routes of infection; (5) age and sex-dependent susceptibility to infection; (6) kinetic of the humoral response to specific and non-specific treponemal antigens; (7) appearance of autoantibodies and immune complexes; (8) cellular response, including lymphoproliferative response, macrophage inhibitory factor(s) production, chemotaxis and adoptive transfer of immunity by purified T cells; and (9) a complete list of references.