The major cause of increased tissue-type plasminogen activator (t-PA) activity during orthotopic liver transplantation (OLT) is still unclear. Both lack of hepatic clearance of t-PA in the anhepatic period and/or increased endothelial release from the graft upon reperfusion have been suggested. Heterotopic liver transplantation (HLT) avoids resection of the host liver and is therefore a useful model to differentiate these two possibilities. The fibrinolytic system was evaluated in ten patients with OLT and in 18 patients with HLT. A marked increment in t-PA activity was observed during the anhepatic period of OLT, which rapidly normalized after reperfusion. In contrast t-PA activity levels remained normal in HLT. As a reflection of the increased t-PA activity fibrin degradation products were markedly elevated during OLT and plasminogen and alpha2-antiplasmin decreased simultaneously during the anhepatic period. In conclusion, the lack of hepatic clearance during the anhepatic period is the most important factor in the evolution of increased t-PA activity during OLT.