Increased numbers of T cell receptor (TCR)-/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-/cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-/cells in anti–HSV-1 immunity, TCR-/ mice treated with anti–TCR-/monoclonal antibodies or TCR-/ TCR-/double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-/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-/cell–mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-/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-/cells may play an important regulatory role in human HSV-1 infections.