Previous studies have validated the capacity of classical (HLA-A,B,C) and nonclassical (HLA-G) MHC class I antigens expressed by target cells to influence natural killer (NK) cell-mediated cytolysis. Generally, elevated expression of these HLA class I molecules is correlated with enhanced resistance to lysis by NK cells. In this study, we have evaluated the effect of transfected class I-like CD1A, CD1B, and CD1C molecules on C1R (HLA-A,B null) target cell sensitivity to natural killing. We report that while each of these molecules was expressed at physiologically relevant levels on the cell surface of clonal transfectants, no change was observed in target cell susceptibility to fresh or lymphokine-activated NK-mediated lysis.