Normal human lymphocyte preparations were tested for their ability to lyse both antibody-coated and unsensitized human target cell lines. The capacity to induce these two types of cell-mediated cytotoxicity, antibody-dependent (Ab-CMC) and spontaneous (Sp-CMC), was detected by a 51Cr release assay. The reactivity of lymphocytes from 1. individual donors showed a positive and highly significanlty correlation between Ab-CMC and Sp-CMC, leading to the hypothesis that the same type of effector cell is involved in the two cytotoxic mechanisms. Lymphocytes from male donors were about twice as effective as those from female donors in both systems. Moreover, the effector cells from male donors carrying HLA antigens A3 and B7 displayed a significantly lower reactivity in both Sp-CMC and Ab-CMC when compared with lymphocytes from male donors bearing any other HLA haplotype. The possible significance of the hyporeactivity of lymphocytes from normal subjects with HLA-A3,B7 haplotype in relation to an increased susceptibility to multiple sclerosis (MS) is discussed.