Sorafenib is the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC); however, its therapeutic value in patients with HCC following resection remains controversial. The current retrospective study was undertaken to assess the effects of sorafenib treatment following surgical resection in patients with advanced HCC disease who were at a high risk for recurrence. Between July 2010 and July 2013, a consecutive cohort of 42 patients with advanced HCC and at a high risk of recurrence (i.e., those with portal vein tumor thrombosis, adjacent organ involvement or tumor rupture) who underwent resection were analyzed. The patients were categorized into the sorafenib group (n=14) or the best supportive care (BSC) group (n=28). Although the histological grade, Barcelona Clinic Liver Cancer Stage, tumor size, nodule number and proportion of patients with high serum a-fetoprotein levels were comparable between the sorafenib and BSC groups, those receiving sorafenib following resection had significantly longer disease-free survival (DFS) of 5.2 months [95% confidence interval (CI), 1.2-9.2 months] compared with the BSC group [1.8 months (95% CI, 0.6-3.0 months)]. No differences in overall survival were noted between the groups. Furthermore, no drug-related adverse events resulted in discontinuation of sorafenib therapy. Univariate log-rank analysis revealed that sorafenib treatment (P=0.002) and treatment prior to resection (P=0.012) were significantly associated with longer DFS; however, sorafenib therapy (P=0.027) and tumor size (P=0.028) were associated with longer DFS by multivariate analysis. Furthermore, sorafenib was well-tolerated and improved DFS in patients with advanced HCC who underwent hepatic resection. Thus, tumor resection followed by sorafenib therapy may represent an effective therapeutic strategy for patients with advanced HCC. This possibility should be confirmed in larger, multicenter studies.