Objective To investigate the relationship between genetic variation of super⁃enhancer region and overall survival（OS）of postoperative patients with hepatitis B virus（HBV）related hepatocellular carcinoma （HCC）. Methods A total of 866 patients HCC who underwent hepatectomy in Guangxi Medical University Cancer Hospital from July 2007 to December 2017 were studied. The relationship between genetic variation of super enhancer region and OS were analysed using Kaplan⁃Meier analysis and Cox proportional hazards regression model. Results The rs61805159（G > A）and rs4791170（G > A）A allele were associated with higher risk of death in patients with HCC（P < 0.001），whereas rs546220（C > A）A allele was associated with a lower risk of death（P < 0.001）. Moreover，patients with multiple risk genotypes had a lower survival rate and a higher risk of death mortality risk than those with 0 risk genotypes，and there was a dose⁃response relationship（Ptrend < 0.001）. Conclusion Single or multiple genetic variation of loci in the super⁃enhancer region affected OS of patients with HCC.