&NA;To better understand the regulation of tissue plasminogen activator (t‐PA) and plasminogen activator inhibitor 1 (PAI‐1) during liver transplantation, we used a computer model of the human circulatory system to simultaneously evaluate the effect of t‐PA secretion, t‐PA inhibition by PAI‐1, hepatic clearance of t‐PA, blood loss, transfusion and hemodynamics on t‐PA and PAI‐1 levels during liver transplantation in three patients that differed in severity of liver disease, blood loss and anhepatic changes in t‐PA. Higher preoperative t‐PA levels were primarily related to underlying liver disease and reduced hepatic clearance. During the anhepatic stage, when hepatic t‐PA clearance was eliminated: (1) the expected rise in t‐PA was modulated by the extent of bleeding, which acted as an alternate t‐PA clearance mechanism; and (2) the ratio of t‐PA:PAI‐1 was increased due both to lower t‐PA clearance and reduced PAI‐1 secretion. Recirculation of the new liver was associated with renewed clearance of t‐PA, an acute phase increase in PAI‐1 and a drop in the t‐PA:PAI‐1 ratio. Understanding fibrinolytic regulation required simultaneous analysis of t‐PA secretion, inhibition and clearance. Anhepatic t‐PA levels could be predicted based on preoperative liver function and surgical blood loss, which acted as an alternate t‐PA clearance mechanism.