T he cellular basis of the impaired autologous mixed leukocyte reaction (AMLR) in patients with systemic lupus erythematosus (SLE) was investigated. Non-T cells from normal subjects and from SLE patients were fractionated into low and high density subpopulations. SLE patients were found to have an increased proportion of low density to high density non-T cells when compared to normal subjects. Although normal low-density non-T cells were highly enriched in AMLR stimulatory capacity, SLE low-density non-T cells induced minimal proliferation by autologous T cells. Brief incubation of SLE non-T cells with phorbol myristate acetate or formalin-treated Staphylococcus aureus resulted in marked augmentation of the capacity of those non-T cells to stimulate an AMLR, although the magnitude of the activated non-T cell-induced AMLR did not achieve that observed in normal subjects. No significant alterations in the expression of Ia molecules on the surface of the non-T cells were detected after in vitro activation. These experiments support the hypothesis that the impaired capacity of SLE T lymphocytes to proliferate in response to autologous non-T cells may in part represent a failure of SLE non-T cells to present an appropriate stimulus for the generation of a T cell response.