Abstract Background During the last decade, cryosurgery became an interesting alternative in the treatment of nonresectable liver neoplasms. The freeze–thaw procedure, however, may be associated with life-threatening thrombocytopenia due to local platelet trapping, and success of neoplasm ablation may be compromised by inadequate parenchymal cell destruction. Methods Because aprotinin is capable of inhibiting the initiation of both coagulation and fibrinolysis, we studied—by whole body scintigraphy of Indium-111–labeled platelets and histomorphology in a porcine model of hepatic cryosurgery—whether this serine protease inhibitor is effective in attenuating platelet trapping and in improving tissue destruction. Results Fifteen minutes of cryotherapy (−168°C at the tip of the cryoprobe) induced a 30 ± 4 cm 3 cryolesion, which presented with massive platelet trapping (14.0 ± 1.7% cryolesion activity/whole body activity) and incomplete parenchymal cell destruction (0.9 ± 0.3; score of hepatocyte nuclear destruction within the margin of the cryolesion). Aprotinin treatment with 500,000 IU initial bolus injection and additional 500,000 IU infusion over 3 hours did not affect the size of the cryolesion (29 ± 3 cm 3) but reduced local platelet activity (1.9 ± 1.9%; P<.001) and induced hepatocyte nuclear destruction (3.0 ± 0.0; P<.001). Conclusions Thus, our study indicates that aprotinin inhibits cryoablation-associated platelet trapping and improves tissue destruction. The serine protease inhibitor may represent a valuable adjunct in cryosurgery of hepatic neoplasms.