Abstract Spontaneous cell-mediated cytotoxicity against Chang cells (a human polyploid liver cell) was demonstrated in a population of healthy volunteers. Cytotoxicity is independent of antibody or secreted factors and is a rapidly occurring event which is initiated by cell contact between the effector and the target cell. The cytotoxic cell is a nonadherent, non-thymus-derived Fc receptor-bearing lymphocyte which lacks surface immunoglobulin. No relationship between antibody-dependent cellular cytotoxicity and spontaneous cell-mediated cytotoxicity against Chang cells was observed, indicating that different cells may mediate these two cytotoxic reactions. The wide range of observed cytotoxic values in different individuals suggests that genetic factors may play a role in spontaneous cell-mediated cytotoxicity.