Lymphokine activated killer (LAK) cells, which arise from interleukin-2 (IL-2) activation of natural killer (NK) cells, are capable of lysing NK-resistant cell targets, including endothelial cells (EC). Since EC cytotoxicity is postulated to play a role in the pathogenesis of systemic sclerosis (SSc), experiments were performed to measure LAK activity in the peripheral blood lymphocytes (PBL) of 10 SSc patients and 10 normal controls. SSc patients had no significant spontaneous cytotoxicity against NK-resistant cell targets, including EC. After IL-2 stimulation in vitro, SSc patients and normal controls demonstrated cytotoxicity toward NK-resistant cell targets, including EC. This LAK-mediated EC cytotoxicity was actually lower for SSc patients than for normal controls. These studies do not preclude a role for LAK-mediated EC cytotoxicity in the pathogenesis of SSc, but demonstrate that LAK cells are not spontaneously present in circulating PBL.