We have previously shown that female outbred CF-1 mice are susceptible to prolonged genital tract infection with the oculogenital serovars (D-K) of Chlamydia trachomatis, and that partial homotypic and heterotypic protection against reinfection is induced. To understand the possible role of inherent T-helper 1 (Th1)/Th2 polarity bias on both the course of infection and the level of acquired immunity induced by infection, 2 immunologically different and well-characterized inbred strains of mice, BALB/c and C57BL/6, were studied in this model. Groups of mice were inoculated intravaginally with C. trachomatis serovar D (Ct D) and monitored by culture to determine the duration of initial infection. Two months later, mice were reinfected, and monitored along with age- and condition-matched control groups. Plasma and vaginal secretions were collected for serologic analysis and specific delayed-type hypersensitivity was assessed by footpad swelling. Initial infection in C57BL/6 mice was comparable in duration to outbred CF-1 mice (median duration 42 versus 43.5 days), while BALB/c mice had a shorter median duration of initial infection (12 days). All strains had significantly shorter durations of infection following reinfection. BALB/c mice shed 4-10 times more inclusion-forming units (IFU) than both C57BL/6 and CF-1 mice on sample days during the first week of infection and all strains shed less IFU during reinfection. C57BL/6 and BALB/c mice had significantly lower anti-Ct D immunoglobulin G titers in both plasma and vaginal secretions than CF-1 mice following resolution of infection; the frequency of immunoglobulin A seropositive vaginal secretions was less in both inbred strains, being significantly less in the case of C57BL/6 mice. Qualitative analysis of the antigen specificity and isotype composition revealed differences among the mouse strains. All 3 strains had detectable levels of specific footpad swelling on day 14 of infection, whereas only BALB/c mice showed a significant response at 70 days post-infection. Significant differences between 2 strains of mice that differ in Th1/Th2 polarity bias were observed in: 1) the duration of infection; 2) the level of bacterial shedding during infection; and 3) the quantitative and qualitative cellular and humoral responses made in response to female genital tract infection with a human oculogenital isolate of C. trachomatis. In addition, a similar and significant level of partial acquired immunity to reinfection was observed in both strains, suggesting that inherent Th1/Th2 polarity bias present upon initial infection does not prevent the development of a protective immune response within the genital tract during infection with an oculogenital isolate of C. trachomatis.