Herpes simplex virus type 1 (HSV-1) stimulation of peripheral blood lymphocytes from patients (PBL-P) with both recurrent corneal and oral-facial HSV-1 lesions results in altered natural killer (NK) activity. Freshly isolated PBL-P exhibit high lysis of HSV-1 infected allogeneic fibroblasts but low lysis of uninfected fibroblasts. After stimulation with HSV-1, PBL-P exhibit markedly increased lysis of uninfected fibroblasts such that the HSV-1 infected and uninfected fibroblasts are lysed with equal efficiency. The NK activity in freshly isolated PBL-P is mediated by effector cells that are phenotypically distinct from those responsible for the NK activity in HSV-1 stimulated PBL-P. In freshly isolated PBL-P most of the lysis of HSV-1 infected fibroblasts is mediated by lymphocytes expressing the phenotype OKM1+, OKT3+, and Leu-7+. After incubation with HSV-1, most of the lysis of HSV-1 infected and uninfected fibroblasts is mediated by lymphocytes that express the OKM1 antigen but lack detectable OKT3 or Leu-7 antigens. The change in function and phenotype appears to reflect in part the activation of Leu-7-, OKM1+, and OKT3- precursors of cytotoxic lymphocytes that are inactive in freshly isolated PBL-P.