The role of cell-mediated immunity in the resistance of young adult mice to subcutaneous herpes simplex virus (HSV) type I infection was studied in mice receiving immunosuppressive doses of antilymphocyte sera (ALS) or antithymocyte sera (ATS). The effectiveness of these treatments to reduce cell-mediated responses was measured by their ability to prolong the life of allografts transplanted to ALS- or ATS-treated mice. It was found that subcutaneous infection of these mice with HSV resulted in spread of virus from the site of inoculation to the central nervous system. Neutralizing antibody could not be detected in the sera of ALS- or ATS-treated mice after HSV inoculation. Passive transfer of neutralizing antibody to ATS-treated mice did not restore resistance to subcutaneous HSV infection. However, adoptive transfer of HSV-sensitized spleen cells did provide significant protection against infection unless the spleen cells were treated with ATS prior to transfer. These experiments suggest that lymphocytes are involved in a cell-mediated response to subcutaneous HSV infection and demonstrate the importance of a noncompromised immune response in controlling spread of HSV from localized areas of infection.