The protective capability of autologous anti-herpes simplex virus type 1 (anti-HSV-1) antibody was analyzed in immunosuppressed mice. Immunologically naive, immunosuppressed mice infected with a low-passage clinical HSV-1 isolate developed local site lesions, monoplegia, paraplegia, and died within 8 days. Mice that had recovered from a previous HSV-1 infection and were immunosuppressed with cyclophosphamide and then rechallenged with live virus showed no symptoms and survived. Untreated mice that had recovered from infection (primed mice) had high titers of anti-HSV-1 antibody and a delayed type hypersensitivity (DTH) response to virus challenge. Cyclophosphamide treatment, but not lethal irradiation, could ablate the DTH response, resulting in a lack of antivirus cell-mediated immunity. Antibody was the only demonstrable protective immune function in the cyclophosphamide-treated animals. This indicates that cell-mediated immunity is not required for protection against HSV-1 challenge in individuals with virus-specific antibody.