An immunoglobulin A (IgA) knockout (KO) mouse was used to study the role of IgA in protective immunity against vaginal infection with herpes simplex virus-type 2 (HSV-2). Intact and KO mice were immunized intravaginally (IVAG) with attenuated HSV-2, challenged IVAG with wild-type virus 6 weeks later and evaluated for vaginal infection and neurological disease. Non-immunized/challenged intact and KO mice showed vaginal infection and succumbed to neurological disease, while immunized/challenged mice exhibited reduced or no vaginal infection and no neurological disease. Log 2.5 enzyme-linked immunoassay (ELISA) titres of viral IgA, immunoglobulin G (IgG) and immunoglobulin M (IgM) in vaginal secretions collected from intact immune mice before challenge were 0.6 ± 0.3, 6.4 ± 0.32 and 0.0, while those in KO immune mice were 0.0, 6.7 ± 0.19 and 3.0 ± 0.29, respectively. Twenty-four hours after challenge, the percentage of vaginal epithelium that was infected in non-immune intact and KO mice was 2.0 ± 0.6 and 2.4 ± 0.6, which was reduced to 0.2 ± 0.1 and 0.1 ± 0.06 in immune intact and KO mice, respectively. No shed virus protein was detected in vaginal secretions 3 days after challenge in any immune mouse, whereas titres were 1400 and 1700 in the two groups of non-immune mice. Thus, immune protection against vaginal HSV-2 infection was similar in both KO and intact mice, indicating that this mucosal immunity does not depend mainly on IgA.