The corneal destruction associated with herpes simplex keratitis (HSK) is primarily the result of the host's immune response to herpes simplex virus type-1 (HSV-1) infection. We examined the role of T cells and T cell subsets in the pathogenesis of HSK. Naive and immune T cells and HSV-1 immune CD4+ and CD8+ subsets from Igh-1 disparate BALB/c congenic mice were adoptively transferred into athymic BALB/c nude mice, which normally do not develop HSK. The results demonstrated that while the transfer of naive T cells from either HSK-susceptible C.AL-20 (Igh-1d) or HSK-resistant C.B-17 (Igh-1b) mice had little influence on HSK development, transfer of either CD3+ or CD4+ HSV-1 immune T cells from C.AL-20 mice resulted in the development of severe HSK in all of the recipients. Transfer of the same cell populations from C.B-17 mice resulted in the development of only a mild keratitis in 50% of the recipients. Transfer of CD8+ cells from either donor strain did not result in stromal disease in any recipient mouse. These results clearly demonstrate the pivotal role of CD4+ T cells in the development of necrotizing herpes stromal keratitis, and further demonstrate that CD8+ T cells are not essential in HSK development in the BALB/c system.