An IgG2a monoclonal antibody (Mab) directed against glycoprotein D of herpes simplex virus 2 (HSV-2) was compared with an IgA heavy chain Mab switch variant to investigate the effect of isotype for topical immunoprotection of the murine vagina. The IgA Mab, a mixture of monomeric and polymeric IgA, was indistinguishable from its IgG parent in an in vitro HSV-2 neutralization assay. When these class switched Mabs were delivered to the mouse vagina, we also found no significant difference between the IgG and IgA for preventing vaginal transmission of HSV-2 infection. The implications of these results for active and passive immunization strategies against vaginal transmission of genital herpes infections are discussed.