Case reports suggest that the course of syphilis is altered in patients infected with human immunodeficiency virus (HIV). To investigate this issue, a model of syphilis in rhesus macaques with and without simian immunodeficiency virus (SIV) was developed. After intradermal inoculation with Treponema pallidum, 2 SIV-infected monkeys had persistent ulcerative primary lesions and 1 developed secondary syphilis. Two SIV-uninfected controls developed transient nonulcerative primary lesions. Only the controls showed consistent VDRL antibody responses. In contrast, reciprocal antibody titers to T. pallidum detected by microhemagglutination were higher in SIV-infected animals (greater than or equal to 20,480) than controls (greater than or equal to 1280). All 4 animals developed a full range of T. pallidum antigen-specific antibodies shown by immunoblot and had similar peak lymphocyte proliferative responses to T. pallidum antigens. These results support the contention that retrovirus-induced immunodeficiency delays clearance of T. pallidum from sites of infection and may impair the humoral immune response to syphilis.