The autologous and allogeneic mixed lymphocyte reactions (MLR), observed when peripheral blood mononuclear cells from 20 patients with progressive systemic sclerosis were used, were compared with those of age-, sex-, and race-matched normal controls. Such cells were separated by gradient centrifugation of sheep red blood cell (E) rosettes into stimulator (E- or non-T cell) and responder (E + or T cell) populations. The autologous MLR of both the progressive systemic sclerosis and normal peripheral blood mononuclear cells varied widely but there was no statistical difference between the means of each group. In the allogeneic MLR, proliferation between progressive systemic sclerosis non-T cells and normal T cells was significantly less than that of normal non-T cells and progressive systemic sclerosis T cells (P = 0.001). A decreased autologous MLR, while noted with other autoimmune diseases, was lacking in progressive systemic sclerosis. This suggests a different defect. The differences in the allogeneic MLR also suggest that either progressive systemic sclerosis non-T cells were poor stimulators or T cells associated with this disease were better responders when compared with similarly prepared cell populations from normal individuals. The MLR differences could have also resulted from compositional subset alterations or the sharing of a common antigen. HLA-DR5 was found in 9 of the 17 white patients with progressive systemic sclerosis. Although these individuals were evenly distributed as low, medium, and high responders, this finding showed that some progressive systemic sclerosis non-T cells shared a common antigen.