Three black Jamaicans with systemic lupus erythematosus (SLE) were identified whose T helper/inducer cells lacked the T4 epitope (T4 epitope-deficient phenotype). All three patients had lymphadenopathy as part of their syndromes. The asymptomatic and otherwise healthy T4 epitope-deficient brother of one of these patients also had lymphadenopathy in a distribution identical to that of his sister with SLE. Family studies pointed to an autosomal codominant mode of inheritance not linked to the HLA locus for the T4 epitope phenotype. Cultures of peripheral-blood mononuclear cells revealed impaired B-cell differentiation upon stimulation with pokeweed mitogen in cells originating from the T4 epitope-deficient family members as compared with those originating from their T4 epitope-intermediate relatives. Ratios of T helper/inducer cells to T suppressor/cytotoxic cells, the presence of various autoantibodies, and proliferation in response to mitogens and in the mixed lymphocyte reactions did not correlate with T4 epitope phenotype. We suggest that SLE in association with the T4 epitope-deficient phenotype may represent a unique subset of patients with SLE that has distinct clinical and immunologic properties.