Recent evidence suggests that transferrin has immunoregulatory functions. In the nephrotic syndrome, excessive urinary losses can produce hypotransferrinemia. Whether low serum transferrin concentration in children with the nephrotic syndrome is related to their decreased immunoglobulin concentrations and to the decreased in vitro response of lymphocytes to a mitogen was studied. Twenty patients, 2 to 15 years of age, were studied. Fifteen patients had the nephrotic syndrome and 5 had other renal disorders. Of 13 patients with nephrotic syndrome in relapse, serum transferrin and gamma-globulin concentrations were decreased in 10 and 11 patients, respectively. Transferrin levels correlated with the concentrations of total protein (r = 0.87, P less than 0.001), albumin (r = 0.91, P less than 0.001), and gamma-globulin (r = 0.78, P less than 0.001). Urinary electrophoretic analyses suggested that hypogammaglobulinemia was not explained simply by urinary losses. In order to determine whether decreased serum transferrin concentrations might limit immunoglobulin synthesis, the effect of hypotransferrinemic sera on lymphocyte proliferation in vitro was tested. At low concentrations of serum, tritiated thymidine uptake was directly proportional to the serum transferrin concentration (r = 0.86, P less than 0.001 at 0.02% serum concentration). Addition of transferrin completely restored the ability of patients' sera to support lymphocyte proliferation. These results suggest that hypotransferrinemia might influence in vivo lymphocyte function and immunity in the nephrotic syndrome.