Mucosal immunity to Chlamydia trachomatis in a mouse model of female genital tract infection is mediated predominantly by Th1-type cells, as shown by in vivo neutralization of cytokines involved in the Th1 vs Th2 pathways. Neutralization of IL-12 was associated with an apparent decrease in the infiltration of CD4+ T cells into infected tissues, systemic reductions in the production of IFN-gamma, and prolonged shedding of high levels of bacteria. Neutralization of IL-4 had no detectable effect on host immunity or on bacterial clearance. To dissociate the protective role of IL-12 from that of IL-12-induced IFN-gamma, resistance to C. trachomatis was compared in IL-12-depleted and IFN-gamma-deficient animals. IL-12-depleted mice displayed minimal bacterial clearance for 1 mo post-infection but eventually resolved genital tract infections completely. IFN-gamma-deficient mice, on the other hand, cleared 99.9% of genital Chlamydia within the first 3 wk but then developed systemic disease associated with dissemination of bacteria to multiple organs. Animals surviving this stage often maintained low level persistent infections within the urogenital tract. These results indicate that the bulk of chlamydial clearance from the genital mucosa is mediated by an IL-12-dependent, IFN-gamma-independent mechanism, while prevention of disseminated disease requires the action of IFN-gamma.