Freshly isolated peripheral blood lymphocytes from patients (PBL-P) with recurrent herpetic corneal and skin lesions, and controls (PBL-C) with no recollection of herpetic disease, effectively lysed herpes simplex virus type 1 (HSV-1) infected but not uninfected allogeneic fibroblasts. However, after 48 hr of stimulation with HSV-1, the lytic activity of PBL-C declined, while that of PBL-P increased. PBL-P and PBL-C produced similar amounts of interferon when stimulated with HSV-1. Thus, the decline in lytic activity by HSV-1 stimulated PBL-C was not due to a lack of interferon production. Interestingly, the lytic activity of HSV-1 stimulated PBL appeared to be directed against a component commonly expressed on both uninfected and HSV-1 infected fibroblasts. This was indicated by the fact that after incubation with HSV-1, PBL-P lysed the uninfected fibroblasts as effectively as the HSV-1 infected fibroblasts. The augmented lysis of uninfected fibroblasts was not due to infection of the "uninfected fibroblasts" by HSV-1 carried over or produced by the HSV-1 stimulated PBL. Furthermore, the capacity of HSV-1 to augment lytic activity was not diminished markedly by ultraviolet irradiation, suggesting that augmentation is due to the stimulatory capacity rather than the infectivity of the virus. Our data show that interaction of PBL-P with HSV-1 results in enhancement of nonspecific lytic activity and loss of the capacity to discriminate HSV-1 infected from uninfected allogenic fibroblasts.