OBJECTIVE To determine the ability of T lymphocytes and natural killer (NK) cells from patients with systemic sclerosis (SSc) to respond to cytokines and to generate immune effector cells. METHODS The numbers and percentages of peripheral blood T and NK cells were examined by 2-color flow cytometry, and NK and lymphokine-activated killer (LAK) cell function were measured in 4-hour 51Cr-release assays, in 34 patients with SSc. The patients were categorized into 3 subgroups: 10 had diffuse cutaneous disease of less than or equal to 3 years disease duration, 11 had diffuse cutaneous SSc of greater than 3 years duration, and 13 had limited cutaneous disease. RESULTS Baseline and activated NK and T cell numbers and NK activity were normal in SSc patients. However, mean LAK activity was significantly depressed in all SSc subgroups. CONCLUSIONS Decreased LAK cell function, despite normal numbers of circulating T and NK cells, indicates that SSc patients have poor ability to produce effector cells in response to interleukin-2.