In order to clarify the role of natural cytotoxicity (NC) in the damage of epidermal keratinocytes (EK) in pemphigus vulgaris (PV) we used the direct 51Cr-release assay in studying the cytotoxic activity of large grandular lymphocytes (LGL), obtained from 34 acute PV patients and 19 healthy donors against EK of PV patients, donors, intact newborn BALB/c mice and mice with experimental PV, shedding and non-shedding grass snakes. We also investigated the effect of pemphigus antibodies and shedding snake serum protein (SSSP) upon EK sensitivity to cytotoxic effects of NC effectors. In other experiments, studied were the amount of serine proteinase secreted by donor LGL in the presence of membrane antigen of antibody- or SSSP-transformed EK, and direct effect of pemphigus antibodies and SSSP upon the release of radioactive label and endoproteinases from EK. It was found that EK, which had interacted with pemphigus antibodies or SSSP, became a sensitive target for NC effectors. Membrane antigen of antibody- and SSSP-transformed human, murine and snake EK induces the secretion of endproteinases by NC effector cells. The conclusion was made that the effect of both pemphigus antibodies and SSSP on EK resulted in the emergences of a new antigen on EK cellular membrane which is recognized by NC effectors and plays the role of the ligand in receptor/ligand interaction between LGL and their targets.