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Abstract: Introduction: The purpose of this study was to estimate, in patients undergoing cardiopulmonary bypass (CPB), the in vivo rates of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) secretion, plasmin generation, fibrin degradation, and plasmin inhibition by aprotinin versus antiplasmin. Materials and methods: Estimates of in vivo rates were based on measured levels of tPA, PAI-1, antiplasmin, plasmin–antiplasmin complex (PAP), total aprotinin, plasmin–aprotinin complex and D-dimer, combined with a computer model of each patient''s vascular system that continuously accounted for secretion, clearance, hemodilution, blood loss and transfusion. Plasmin regulation was studied in nine control patients undergoing CPB without aprotinin versus six patients treated with aprotinin. Results: In controls, plasmin–antiplasmin levels rose from a baseline of 3.0±0.9 to a peak of 8.1±2.7 nmol/L after CPB due to an average 44-fold rise in the plasmin generation rate. This rise in plasmin generation during CPB lead to increased fibrin degradation causing D-dimer levels to increase from a baseline of 1.2±0.6 to a peak of 9.7±4.4 nmol/L due to an average 74-fold rise in the D-dimer generation rate. During CPB in the aprotinin group, plasmin–antiplasmin levels dropped, plasmin–aprotinin complex levels rose, while D-dimer levels remained unchanged from baseline. Compared to controls, the aprotinin group showed similar rates of plasmin generation during CPB, but an 11-fold faster plasmin inhibition rate and a 10-fold lower D-dimer generation rate. Conclusions: The rise in plasmin generation and fibrin degradation that occurs during standard CPB is suppressed by the addition of aprotinin, which returns the patient to near baseline fibrin degradation rates during CPB. [Copyright &y& Elsevier]