AbstractThe plasmin and plasminogen activator proteases of the plasma fibrinolytic system were investigated as potential blood‐borne mediators of the proliferative activation of hepatocytes by partial hepatectomy. Partial (68%) liver resection, as well as proliferatively activating the remaining hepatocytes, rapidly (by 30 minutes) doubled the level (or activity) of circulating plasminogen activator but later (2 hours) greatly depressed this level. This later depression of the activity of circulating plasminogen activator lasted for eight to ten hours before returning to the normal level two to four hours before the hepatocytes in the liver remnant began to synthesize DNA. This sequence of changes in the fibrinolytic potential was not abolished by prior thyroparathyroidectomy which is known to inhibit the initiation of hepatocyte DNA synthesis and to prevent the secretion of the calcium homeostatic hormones, another early systemic consequence of partial liver resection. Since the early rise in plasminogen activator activity did not cause the appearance of active (free) circulating plasmin, and since the injection of large doses of the fibrinolytic and protease inhibitors, EACA and Trasylol®, during this early, post‐operative period of hyperfibrinolytic potential did not prevent hepatocytes from initiating DNA synthesis, it is unlikely that either plasmin or its activator protease are blood‐borne initiators of hepatocyte proliferative development.