Whether there is a pathogenic or protective outcome to chlamydial infection may be defined by the host response. We infected C57BL/6 (C57) and C3H/HeN (C3H) mice with the human biovar of Chlamydia trachomatis, serovar E, and, in select experiments, with the mouse pneumonitis agent of C. trachomatis (MoPn). We compared the courses of infection, histopathology, and host responses that resulted from these infections. The duration of infection with either chlamydial biovar was significantly increased in the C3H strain of mice. The intensity of infection was examined in mice infected with serovar E, and it was significantly increased in the C3H strain. Histopathology revealed the incidence of severe hydrosalpinx to be significantly greater in C3H mice than in C57 mice. In contrast, severe distention of the uterine horns was observed in all infected C57 mice compared to none of the C3H mice infected with serovar E and only 25% of those infected with MoPn. Acute inflammation was significantly increased in the uterine horns of C57 mice compared to that of C3H mice. Examination of antigen-specific responses revealed qualitatively similar responses in the two strains. Determination of gamma interferon- versus interleukin 4- producing cells revealed the predominance of a Th1 response in both strains. Serum enzyme-linked immunosorbent assays for immunoglobulin G1 (IgG1) and IgG2a revealed a predominance of IgG2a antibody in both strains, although the levels of antibody were significantly greater in C3H mice. Lymphocyte proliferation studies revealed increased proliferation in the iliac nodes of both strains at 1 to 3 weeks after infection. Because of the early eradication of infection observed in the C57 strain, we explored the relative production of tumor necrosis factor alpha (TNF-alpha) in the two strains. TNF-alpha levels were significantly increased in the genital tract secretions of C57 mice compared to that of C3H mice during the first week of infection. Increased TNF-alpha may be beneficial to the host by leading to earlier eradication of infection, thereby preventing infection of the oviduct and thus the major disease sequelae associated with chlamydial infection of the genital tract.