BACKGROUND: Interferon-gamma acts to multiply the potency with which innate interferons (alpha/beta) suppress herpes simplex virus type 1 (HSV-1) replication. Recent evidence suggests that this interaction is functionally relevant in host defense against HSV-1. However, it is not clear which WBCs of the innate immune system, if any, limit HSV-1 spread in an IFN-gamma dependent manner. The current study was initiated to determine if natural killer (NK) cells provide innate resistance to HSV-1 infection, and if so to determine if this resistance is IFN-gamma-dependent. RESULTS: Lymphocyte-deficient scid or rag2(-/-) mice were used to test four predictions of the central hypothesis, and thus determine if innate resistance to HSV-1 is dependent on 1. NK cell cytotoxicity, 2. NK cells, 3. WBCs, or 4. the IFN-activated transcription factor, Stat 1. Loss of NK cell cytotoxic function or depletion of NK cells had no effect on the progression of HSV-1 infection in scid mice. In contrast, viral spread and pathogenesis developed much more rapidly in scid mice depleted of WBCs. Likewise, loss of Stat 1 function profoundly impaired the innate resistance of rag2(-/-) mice to HSV-1. CONCLUSION: Lymphocyte-deficient mice possess a very tangible innate resistance to HSV-1 infection, but this resistance is not dependent upon NK cells.