Removal of herpes simplex virus (HSV)-infected cells from peripheral sites such as the skin is mainly an activity of T cells, particularly the CD4+ T subset. Such cells orchestrate an inflammatory response with interferon-gamma (IFN-gamma) appearing to play the essential role in viral clearance. In accordance with this hypothesis, we show that infection of BALB/c background mice expressing the knockout phenotype for IFN-gamma (GKO mice) are significantly more susceptible to the development of cutaneous zosteriform lesions than are wild-type. However, following HSV immunization, GKO mice become solidly immune to the development of zosteriform lesions. In addition, the transfer of T cells from immune GKO mice to nude mice recipients renders them resistant to zosteriform lesions. Our results are discussed in terms of the major and compensatory mechanisms available to the body to effect immunity to viral infections.