Because of evidence of immunoregulatory effects of short-term administration of pooled donor gamma globulins, the effects of intravenous immune serum globulin were studied in nine adult patients with common variable hypogammaglobulinemia over a two-year period. Baseline assessment prior to immune serum globulin replacement included evaluation of B cell function, suppressor cell activity, and T cell subsets. These analyses were subsequently performed during the course of a first-year treatment period of intravenous immune serum globulin at doses of 100 to 200 mg/kg per month and a second-year trial at doses of 300 to 400 mg/kg per month. Five patients were re-evaluated following discontinuation of the intravenous immune serum globulin therapy for four months between the first and second treatment periods. During both treatment periods with intravenous immune serum globulin, suppressor cell activity increased markedly compared with baseline, and declined following discontinuation of drug therapy in the five patients. Suppressor cell activity was reversed by either irradiation of the T cell fraction or removal of the T8-positive cell fraction by flow cytometry. There was a reduction in the absolute number of total lymphocytes, the T3-positive cells (total T cells), and the T4-positive cells (helper cells) following intravenous immune serum globulin therapy; however, the percentages of the T cell subsets did not change significantly. Following immune serum globulin therapy, the number of T8-positive cells was not significantly changed but the T4:T8 ratio decreased from 2.1 at baseline to 1.5 after therapy (p greater than 0.05). These data demonstrate that long-term intravenous immune serum globulin administration modulates the immune system by increasing suppressor T cell functional activity but is not accompanied by changes in the number of T8-positive cells in the peripheral blood.