It is well established that T lymphocytes play a critical role in the control and clearance of herpes simplex virus (HSV) infections. However, the role of the CD4+ and CD8+ T cell subsets in the recovery process has not been clearly elucidated. Cutaneous HSV infection of the footpad tissue of C57BL/6 (B6) mice provides a model to determine the relative contribution of each T cell subset during the important early phase of the response to infection. In this study, we observed that the elimination of mature peripheral T lymphocytes by depletion in vivo with a combination of Cd4- and CD8-specific monoclonal antibodies prevented recovery from acute infection in this model. However, mice depleted of either the CD4+ or CD8+ subpopulation alone recovered completely, with only a slight delay in the total clearance of infectious virus. Adoptive transfer studies revealed that lymph node cells from donor mice selectively depleted of either CD4+ or CD8+ T cell subset in vivo, or from normal donors selectively depleted in vitro, were able to mediate recovery. As CD4-depleted mice fail to generate a CD8+ T cell-mediated cytolytic T lymphocyte (CTL) response, this suggested that the control of cutaneous HSV infections may be mediated by a cytokine-dependent mechanism common to both the CD4- and CD8+ T cell subpopulations. It was subsequently found that the neutralization of IFN-gamma in vivo diminished the ability of mice to clear infectious HSV from the skin, and treatment with anti-IFN-gamma in vivo ablated the ability of transferred T cells to mediate recovery. These studies suggested that IFN-gamma-mediated mechanisms play a critical role in the control of and recovery from acute cutaneous HSV infection.