Increased numbers of T cell receptor (TCR)-γ/δ cells have been observed in animal models of influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-γ/δ cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-γ/δ cells in anti–HSV-1 immunity, TCR-α^−/− mice treated with anti– TCR-γ/δ monoclonal antibodies or TCR-γ/δ × TCR-α/β double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-γ/δ cells limited severe HSV-1–induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection resulted from TCR-γ/δ cell–mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-γ/δ cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-γ/δ cells may play an important regulatory role in human HSV-1 infections.