Experiments were performed to further elaborate on our congenital syphilis rabbit model. Attempts were made to determine whether in utero exposure to Treponema pallidum would stimulate immune reactivity and whether this activity would, in turn, affect lesion development upon challenge infection. Newborn rabbits aged 2 or 5 weeks were obtained from control does or from does infected intravenously with T. pallidum during pregnancy. Congenitally infected newborns exhibited increased immunologic functions. Concanavalin A-induced T-lymphocyte proliferation was elevated at both 2 and 5 weeks. In addition, macrophage Ia expression and RPR antibody titers were increased at 5 weeks. In separate experiments, newborn rabbits from control does or from does infected during pregnancy were challenged intradermally with viable organisms at either 2 or 5 weeks of age. Subsequent lesion severity was markedly increased in those newborns previously exposed to treponemes in utero. These observations further strengthen our model for congenital transmission of T. pallidum during pregnancy. We propose that at least some of the tissue pathology in syphilitic infection is associated with activated host defenses.