Normal human T cells proliferate vigorously when stimulated with autologous non-T cells. This autologous mixed lymphocyte reaction (MLR) between T and non-T cells was defective in patients with active systemic lupus erythematosus (SLE). In contrast, T cells and non-T cells from active SLE patients behaved normally as responding and stimulating cells, respectively, in the allogeneic MLR. The etiology of the impaired autologous MLR was further examined by studying the functional capacity of subsets of stimulating or responding cells. B cells, L cells, and monocytes from active SLE patients failed to stimulate autologous T cells but these cells effectively stimulated allogeneic T cells. Fc(IgG)+ T cells from active patients were unable to respond in both the autologous and allogeneic MLR; their Fc(IgG)-T cells responded well in the allogeneic but not in the autologous MLR. The Fc(IgG)+ T cells, but not the Fc(IgG)- T cells, from inactive SLE patients also failed to respond in the both autologous and allogeneic MLR. These studies indicate that patients with SLE have functionally defective Fc(IgG)+ T cells and a defective autologous MLR, both of which may contribute to impaired regulation of immune functions.