We developed a murine model of systemic infection with Chlamydia trachomatis biovar lymphogranuloma venereum (LGV). The pathological features of this infection resemble those of human LGV infection since both are characterized by granuloma formation. Mice developed resistance to reinfection with LGV, and this resistance was based on cellular immune mechanisms since it was transferable with immune spleen cells but not with immune serum. Resistance required viable organisms for induction. We compared LGV biovar infection with trachoma biovar infection. Trachoma biovar produced similar but less marked microbiological and pathological features. Cross-immunity was less apparent between serovars from trachoma and LGV biovars than it was between serovars within the same biovar. This model of systemic C. trachomatis infection will be useful in exploring virulence features of LGV.