Purpose This phase I study was performed to evaluate coagulation alterations during extracorporeal circulation (ECC) induced whole body hyperthermia (WBHT) in 12 patients with advanced soft tissue sarcomas. Methods To distinguish between effects of normothermic ECC and ECC-WBHT, blood samples were drawn at different time points: at baseline, after 30 min on normothermic ECC, at the end of the heating period, and 24 h and 7 days thereafter. Standard coagulation tests, coagulation factors, thrombelastography, platelets and reticulated platelets, liver enzymes, and scintigraphic platelet imaging were performed. Results Normothermic ECC resulted in coagulation alterations most likely due to systemic anticoagulation. Induction of hyperthermia caused thrombocytopenia, increased fibrin degradation products, prolonged clotting times, alteration in coagulation factors, and increased liver enzymes. The majority of these effects was most pronounced 24 h after ECC-WBHT. In addition, late liver sequestration of platelets was demonstrated in scintigraphic imaging at that time point. Conclusions Temporal correlation between hemostatic alterations and elevation in liver enzymes leads to the assumption that liver impairment might play a crucial role in coagulation disturbances observed during ECC-WBHT and thereafter, thus strongly supported by liver sequestration of platelets. Therefore a close monitoring of hepatic derived coagulation alterations in patients undergoing extracorporeal whole body hypothermia is warranted.