To investigate the pathogenesis of macroglobulinemia in the tropical splenomegaly syndrome (TSS), we assessed the functional activity of B lymphocytes and T cell subsets in a pokeweed mitogen-driven assay of immunoglobulin synthesis. Mononuclear cells from patients with TSS produced more IgM than cells from village or from distant controls. This appeared to result from a decrease in the number and/or activity of suppressor T cells of the T8+ phenotype. The lack of functional suppressor T lymphocytes was associated with the presence in sera from patients with TSS of IgM antibodies that specifically killed T8+, 9.3-, 60.1+ T cells from normal donors. These results support the hypothesis that macroglobulinemia in TSS results from defective immunoregulatory control of B cell function, and that this may be caused by lysis of suppressor T cells by specific lymphocytotoxic antibodies produced by patients with this syndrome.