The p35 molecule is unique to interleukin-12 (IL-12), while p40 is shared by both IL-12 and IL-23. IL-12 promotes Th1 T cell responses, while IL-23 promotes Th17 T cell responses. The roles of IL-12p35- and IL-12p40-mediated responses in chlamydial infection were compared in mice following an intravaginal infection with Chlamydia muridarum. Mice deficient in either IL-12p35 or p40 both developed similar but prolonged infection time courses, confirming the roles of IL-12-mediated immune responses in clearing primary infection. However, all mice, regardless of genotype, cleared reinfection within 2 weeks, suggesting that an IL-12- or IL-23-independent adaptive immunity is protective against chlamydial infection. All infected mice developed severe oviduct hydrosalpinx despite the increased Th2 responses in IL-12p35- or IL-12p40-deficient mice, suggesting that Th2-dominant responses can contribute to Chlamydia-induced inflammatory pathology. Compared to IL-12p35 knockout mice, the IL-12p40-deficient mice exhibited more extensive spreading of chlamydial organisms into kidney tissues, leading to significantly increased incidence of pyelonephritis, which both confirms the role of IL-12 or IL-23-independent host responses in Chlamydia-induced pathologies and suggests that in the absence of IL-12/IFN-γ-mediated Th1 immunity, an IL-23-mediated response may play an important role in restricting chlamydial organisms from spreading into distal organs. These observations together provide important information for both understanding chlamydial pathogenesis and developing anti-Chlamydia vaccines.