The combined effects of orchiectomy and estrogen administration on synthesis of selected hepatic secretory proteins--antithrombin (AT) III, plasminogen, fibrinogen, factor II (prothrombin), factor VII, fibronectin, and albumin--were studied using the isolated rat liver perfused in vitro for ten hours. Male rat liver donors underwent orchiectomy under ether anesthesia and then received 5.0 mg of diethylstilbestrol (DES) by subcutaneous pellet implantation or a placebo pellet; 14 days later the livers were extracted and perfused in vitro for ten hours. In DES experiments, 1.0 mg of DES was also added directly to the liver perfusate at the outset. Pretreatment with DES resulted in significant increases in cumulative synthesis of factors II (65%) and VII (76%) and significant reduction in cumulative synthesis of both antithrombin III (20%; P = .03) and plasminogen (27%; P less than .01) compared to control perfusions, but synthesis of fibrinogen, fibronectin, and albumin was not significantly affected by addition of the hormone. Plasma samples collected from rat liver donors that had received DES showed similar effects on protein concentrations: significant decreases in concentration of plasminogen and antithrombin III were apparent with no significant changes in concentrations of fibrinogen, fibronectin, or albumin. In additional perfusions, “dose- response” experiments were conducted in which rat liver donors received a subcutaneous DES pellet of 0.5, 5.0, or 50 mg. Synthesis of plasminogen in this group of perfusions was progressively decreased as the concentration of DES administered to the rat liver donor increased. Synthesis of AT III was reduced to the same degree by 5.0 or 50 mg of DES, both being substantially lower than the 0.5-mg experiments. Concentrations of these two proteins in plasma samples from rat liver donors showed changes quite similar to those seen in perfusion experiments; however, plasma fibrinogen concentrations were not different among the three groups of rats.