Objective: To investigate the influence of the anterior approach hepatectomy with selective inflow occlusion on the reperfusion injury in the contralateral non-tumor liver tissue and remnant liver function in treatment of huge hepatocellular carcinoma (HCC). Methods: Forty-five patients with huge HCC (≥10 cm in diameter) were divided into observational group and control group using Zelen’s single randomized consent design. Patients in control group underwent the conventional hepatectomy with total hepatic inflow occlusion, while those in observational group underwent anterior approach hepatectomy with selective inflow occlusion and a small contralateral non-tumor tissue specimen was taken from each patient in both groups after tumor removal. The levels of total bilirubin (TBIL), alanine transaminase (ALT) and prealbumin (PA) in the two groups of patients at one week after surgery were measured, and the apoptosis, and the parameters of intracellular calcium ion concentration ([Ca2+]i), malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in contralateral non-tumor tissues were also determined. Results: Compared with control group, the ALT release was decreased and PA level was increased significantly (both P<0.05), while the TRIL level showed no obvious difference (P>0.05) at one week after surgery in observational group; the apoptosis, [Ca2+]i and MDA content was significantly reduced, while the SOD activity was significantly elevated in the contralateral non-tumor tissue in observational group (all P<0.05). Conclusion: Compared with conventional procedure, anterior approach hepatectomy with selective inflow occlusion for huge HCC is superior in reducing reperfusion injury of the contralateral non-tumor liver tissue and improving the function of remnant liver.