At the time of hepatectomy for primary hepatocellular carcinoma (HCC), the necessary amount of surrounding nontumorous liver to be sacrificed, or the resection margin, which will ensure a complete histologic disease clearance is uncertain. Twenty-three resected liver specimens were studied by serial section followed by histological examination prospectively. All histologic diseases identified were assumed to spread radially in all directions from a unicentric lesion. Histologic disease from capsular and liver invasion was found confined to the immediate surrounding liver parenchyma. Eleven of the 14 large (> or = 5 cm) tumors and all six small (< 5 cm) HCCs had either microsatellites and/or histologic venous permeation found beyond 1 cm from the lesion. A large tumor, multinodular lesions, macroscopic venous thrombi, liver invasion, and nonencapsulation were associated with an extensive spread of histologic disease. In the presence of either microsatellites or histologic venous permeation, no distance could ensure a complete disease clearance.