The purpose of this paper is to investigate the natural killer (NK) sensitivity of 15 cell lines derived from human brain tumors expressing different levels of major histocompatibility complex (MHC) antigens. Although it has recently been reported that NK susceptibility varies inversely with target cell class-I human leukocyte antigen (HLA) expression, our results show no correlation between class-I HLA, class-II HLA or beta 2-microglobulin expression on target cells and NK sensitivity, whereas a significant inverse correlation between NK susceptibility and the degree of tumor cell differentiation has been found. Thus, poorly differentiated tumor cells are highly susceptible to NK lysis, whereas well-differentiated ones are NK resistant. These results suggest that sensitivity to lysis by NK cells of cell lines derived from human brain tumors is primarily determined by the stage of differentiation and not by the level of MHC antigen expression on target cell.