The influence of the anatomical location of single large hepatocellular carcinoma (HCC) on outcomes following hepatic resection (HR) is still unclear. This study examined the role of anatomical location profiles as prognostic markers for patients with single large HCC undergoing HR.A total of 374 consecutive patients with single large HCC undergoing HR between January 2009 and July 2013 were included. They were divided into group same section (SS) group (n = 171) and different sections (DS) group (n = 203) according to their tumor's anatomical location. Short- and long-term outcomes were compared between the two groups.More patients in group DS had intraoperative blood loss of >1000 mL and needed intraoperative blood transfusion than those in group SS. There were no significant differences regarding postoperative complications and 30-and 90-day mortality between the two groups. The overall survival (OS) and recurrence-free survival (RFS) rates were significantly higher in group SS than group DS. The subgroup analysis showed that tumor in the same section was associated with better prognosis than those in different sections for both patients with tumor of ≤8 cm and of > 8 cm. Multivariate analysis revealed that age <60 years, portal hypertension, alpha-fetoprotein ≥400 ng/mL, tumor in different sections, microvascular invasion and poorly differentiated tumor are independent predictors of poor prognosis in patient with single large HCC.For patients with single large HCC, a tumor located in the same section may lead to better long-term survival and lower tumor recurrence rates than those in different sections following HR.