The necessary resection margin (RM) for cure during hepatectomy for hepatocellular carcinoma (HCC) remains conjectural. From January, 1972 to June, 1988, a total of 96 patients who had complete macroscopic extirpation of their large tumor (greater than or equal to 5 cm in largest diameter) were studied retrospectively to determine the macroscopic distance of RM required to secure histological disease clearance. Positive histological RM, which was found in 31 (32.3%) patients, had significantly compromised both disease-free survival (p less than 0.04) and overall survival (p less than 0.006) of these patients. Among the 65 patients with detailed measurement of macroscopic RM, a significant reduction of residual histological disease was observed when a 0.5 cm margin had been established (p less than 0.05). Further extension of margin had no additional benefit. The presence of microsatellite (p less than 0.03) and multiple tumor nodules (p less than 0.03) was associated with an increased risk of positive histological margins among the 15 pathological parameters evaluated, including macroscopic RM. Since measurement of RM is an unreliable guide, histological confirmation is the only means for establishing the diagnosis of complete tumor clearance. Within safety limits dictated by anatomical factors and severity of underlying cirrhosis, aggressive surgery should be offered for patients with large HCC; however, resection is not advisable unless a 0.5 cm margin can be secured with certainty, especially for multinodular lesions.