Objective: To evaluate the safety and efficacy of Glissonean pedicle transection method for anatomic mesohepatectomy. Methods: According to frequency-matching principle, 51 patients with central liver tumors were randomly designated to undergo liver resection with conventional procedure (n=30) or Glissonean pedicle transection method (n=21). The operative time, intraoperative blood loss, postoperative liver function, length of hospital stay, incidence of complications and outcomes between the two groups were compared. Results: By comparison with the conventional group, Glissonean pedicle transection group had decreased operative time [(2.7±0.839) h vs. (4.5±0.952) h], reduced intraoperative bleeding [ (406±33.182) mL vs. (793±29.677) mL], fast recovery of liver function [ALT value on postoperative day (POD) 7: (63.048±7.513) U/L vs. (323.667±12.939) U/L], and shortened length of hospital stay [(12.528±0.245) d vs. (16.733±0.338) d], as well as lowered incidence of postoperative complications (14.2% vs. 40%) and 1-year tumor recurrence rate [4.8% (1/21) vs. 26.7% (8/30) ]. All the differences between the two groups had statistical significance (all P<0.05). Conclusion: Glissonean pedicle transection method for anatomic mesohepatectomy is safe, effective, minimally invasive, and is recommended for general use.