Cell-mediated cytotoxicity was examined in thirty-seven patients with systemic sclerosis using both whole blood and purified peripheral blood mononuclear cells (PBM) to measure antibody-dependent (ADCC) and phytohaemagglutinin (PHA) induced lymphocyte cytotoxicity to 51Cr-labelled Chang liver cells. In twenty-three mildly affected patients, ADCC and PHA-induced cytotoxicity did not differ from that found in control populations. By contrast, fourteen patients severely affected by extensive visceral disease showed reductions in both ADCC and PHA-induced cytotoxicity which were more marked in whole blood assays (P less than 0.001) than in those performed with PBM (P less than 0.05). The addition of patient's sera to control cytotoxicity assays suggested that blocking or suppressive serum factors could only account for some of the disproportionate reduction in whole blood cytotoxicity which, in the main, must be due to a lack of circulating effector cells. These results are in agreement with previous findings of reduced numbers of circulating thymus-dependent lymphocytes in patients with severe disease, a defect of cell-mediated immunity that may result from the chronic antigenic stimulation of an autoimmune disease process.