We investigated suppressor and helper T cells in 19 patients with variable immunodeficiency to assess the possibility that defective interactions among these cells and B lymphocytes are the chief cause of the inadequate plasma-cell development and hypogammaglobulinemia characterizing these syndromes. We accomplished functional separation of the two T-cell subsets, using irradiation, which selectively inactivates T-cell suppressors. The patient B lymphocytes were usually capable of some differentiation into plasma cells when co-cultured with T cells manipulated to optimize helper effects. Eighteen of 19 patients showed quantitatively poor plasma-cell production even under these conditions. However, only one had defective enough helper function, and only one sufficiently excessive suppressor activity for these factors to be considered the major pathogenetic process in each case. Since neither an absolute defect in B cells nor consistent abnormalities in modulator T cells were demonstrable in most patients, other explanations must be sought for the mechanisms underlying this form of primary immune deficiency.