The male and female genital tracts are protected by a local immune system that displays features distinguishing them from other mucosal sites. In contrast to the intestinal tract, where locally produced IgA is the dominant Ig, secretions of the male and female genital tract contain predominantly IgG of both local and systemic origin. Genital tract tissues also lack mucosal lymphoepithelial inductive sites analogous to intestinal Peyer's patches; consequently, local immunization or infections with sexually transmitted pathogens induce low immune responses. Human immunodeficiency virus 1 (HIV-1) infection must be primarily considered as a mucosal disease with extensive involvement of the systemic immune compartment. Although the majority of infections is acquired through the genital mucosa, a high rate of virus replication and profound CD4(+) T cell depletion occurs in the intestinal mucosa and other mucosal tissues shortly after infection. Evaluation of HIV-specific antibodies in sera and external secretions, including vaginal washes and semen, unexpectedly revealed a selective lack of IgA responses. Moreover, specific antibody-secreting cells in peripheral blood were of the IgG isotype, even in mucosally infected individuals. Whether humoral responses to previously or newly encountered antigens are compromised in HIV-1-infected persons is under current investigation.