Total vascular isolation (TVI) of the liver was employed during parenchymal transection in 16 patients undergoing hepatic resection for large tumors (mean diameter, 10.7 cm) located near hilar structures, hepatic veins, or the inferior vena cava (IVC). In 14 cases, TVI was achieved by clamping the suprahepatic and intrahepatic IVC and the porta hepatis, with or without aortic occlusion; in two, selective hepatic vein clamping was possible, obviating IVC occlusion. Procedures included standard and extended right and left lobectomies and caudate lobe resections. Concomitant resection and reconstruction of the portal vein (one case), IVC (one case), and bile duct (three cases) was required. Postoperative hepatic and renal failure did not occur. Mean intensive care unit and hospital stays were 2.8 ± 1.9 and 12.5 ± 5.2 days, respectively. There were two perioperative deaths. Total vascular isolation permits safe resection of large, critically located tumors that would otherwise present prohibitive operative risks.