Thioredoxin (TRX), a disulfide-reducing intracellular dithiol enzyme, is synthesized by both normal liver cells and the hepatocarcinoma cell line HepG2. Only the former, however, secrete abundant TRX extracellularly. When cultured in mild reducing conditions, HepG2 cells but not normal hepatocytes increase the rate of TRX secretion and undergo growth inhibition accompanied by morphological changes. Also, recombinant TRX inhibits proliferation of HepG2 cells. In contrast, exogenous thiols and TRX stimulate proliferation of a B-cell lymphoma line, indicating that different cell types respond differently to variations in the extracellular redox potential.