Mice with disrupted  2-microglobulin ( 2 m ؊/؊), I-A (class II ؊/؊), or CD4 (CD4 ؊/؊) genes were examined for their capacity to resolve Chlamydia trachomatis genital tract infection. C57BL/6 and  2 m ؊/؊ mice resolved infection similarly and were culture negative by 4 to 5 weeks following infection. Conversely, major histocompatibility complex (MHC) class II ؊/؊ mice failed to resolve infection, and CD4 ؊/؊ mice showed a significant delay (2 weeks). Secondary challenge of C57BL/6,  2 m ؊/؊ , and CD4 ؊/؊ mice established that acquired protective immunity, which was characterized by an infection of shortened duration and reduced shedding of infectious organisms, developed. Serological analysis of C57BL/6 and  2 m ؊/؊ mice by enzyme-linked immunosorbent assays revealed no striking differences in the immunoglobulin subclass specificity of the anti-Chlamydia response, although some differences were observed in the magnitude of the immunoglobulin G2a (IgG2a) and IgG2b responses. Class II ؊/؊ mice produced lower-titered serum anti-Chlamydia antibodies of all isotypes. The serum antibody responses of CD4 ؊/؊ mice were similar to those of C57BL/6 mice, except that the anti-Chlamydia IgA response was delayed by approximately 3 weeks. Analysis of vaginal washes for Chlamydiareactive antibodies revealed the presence of IgG2a, IgG2b, and IgA in C57BL/6 and  2 m ؊/؊ mice and primarily of IgA in CD4 ؊/؊ mice. Vaginal washes from class II ؊/؊ mice were consistently antibody negative. Interestingly, the Chlamydia-specific IgA response in the vaginal washes of CD4 ؊/؊ mice was delayed, but its appearance coincided with decreased shedding of infectious organisms and resolution of infection. Our results demonstrate that MHC class II-restricted T-cell responses are necessary for the development of protective immunity to Chlamydia genital tract infection and that local (vaginal) anti-Chlamydia IgA antibody coincides with the resolution of infection. A substantive role for MHC class I-restricted T-cell responses in protective immunity to Chlamydia genital tract infection was not confirmed.