Objective: To investigate the application value of high frequency electric knife in liver resection for hepatocellular carcinoma (HCC). Methods: A total of 386 HCC patients were divided into observation group (n=199) and control group (n=187). Liver resection was performed by electric coagulation knife with an output power of 120 W in patients in observation group, and was performed by ultrasonic knife through clamp crushing method in control group. The clinical variables that included time of hepatic inflow occlusion, operative time, intraoperative blood loss, intra- and post-operative transfusion of red blood cells (RBC), postoperative drainage, changes in liver function, postoperative complications, and length of hospital stay were compared between the two groups. Results: Operation was successfully performed in all patients, and no burn injuries or electrocardiographic abnormalities caused by high-power and high-frequency current were noted in observation group. In observation group compared with control group, the operative time (192.79 min vs. 212.10 min), hepatic inflow occlusion time (5.17 min vs. 14.65 min), incidence of postoperative complications (21.1% vs. 34.2%), ratio of postoperative RBC transfusion (25.7% vs. 36.7%) and length of postoperative hospital stay (8.87 d vs. 12.15 d) were all significantly reduced (all P<0.05), but the intraoperative blood loss (378.56 mL vs. 412.75 mL), ratio of intraoperative RBC transfusion (7.5% vs. 7.5%), and time to postoperative tube removal (5.83 d vs. 6.29 d) showed no significant difference (all P>0.05). Some liver function parameters on postoperative day 1 and 3 in observation group were superior to those in control group (all P<0.05). There was no significant difference in postoperative 1-, 2- and 3-year overall survival rates between the two groups (all P>0.05). Conclusion: Using high-frequency electric knife in liver resection for HCC has fast speed of resection and good hemostatic effect, and its use is safe and reliable.