Background: Patients on regular hemodialysis treatment are in an immunodeficiency state. Several studies have shown defective T cell proliferation after stimulation with various agents. Staphylococcal enterotoxin B (SEB) is a MHC-dependent superantigen that triggers proliferation of a large proportion of T cells. T cell activation after stimulation with SEB parallels normal T cell signal transduction. An important and early event in this transduction pathway is the phosphorylation of the ζ chain. In this study, T cell proliferation and ζ chain phosphorylation after stimulation with SEB were evaluated. Methods: Peripheral blood mononuclear cells (PBMCs) from 24 patients and 14 healthy individuals were isolated and cultured with or without stimulation with SEB (1 ng/ml). Cell proliferation was estimated by immunoenzymatic measurement of bromodeoxyuridine uptake. PBMCs from 8 patients and 6 healthy individuals were isolated and pulsed for 2 min with or without SEB (10 µg/ml). ζ chain phosphorylation was estimated by immunoprecipitation and immunoblotting with antiphosphotyrosine antibody. Results: Lymphocyte proliferation index after SEB stimulation was lower in hemodialyzed patients. Stimulation of T cells with SEB also resulted in a lower ζ chain phosphorylation in hemodialyzed patients. Conclusions: Lymphocyte proliferation after MHC-dependent stimulation is impaired in hemodialyzed patients. This proliferation defect is due to impaired ζ chain phosphorylation.