Vaccines designed to prevent mucosal transmission of HIV should establish multiple immune effectors in vaccine recipients, including antibodies which are capable of blocking HIV entry at mucosal epithelial barriers and of preventing initial infection of target cells in the mucosa. Immunological analyses of HIV-resistant humans and data obtained in nonhuman primate vaccine studies indicate that both secretory and serum antibodies may play an important role in protection against mucosal transmission of HIV or SIV, whereas cytotoxic T cells are required for clearance of mucosal infection and prevention of systemic spread. This review summarizes the roles of IgA and IgG antibodies in preventing mucosal infection by other viral and bacterial pathogens, and then discusses the various mechanisms by which antibodies might contribute to protection against HIV at mucosal surfaces. These include prevention of mucosal contact, blocking attachment of virus or infected cells to epithelial cells, interception of virus during transepithelial transport, neutralization of virus in the mucosa, and elimination of locally infected cells through antibody-dependent cell-mediated cytotoxic reactions. The regional nature of mucosal immune responses is reviewed in light of its relevance to HIV vaccine development. We conclude that mucosal immunization should be considered a component of vaccine strategies against HIV.