Due to higher technical requirements, laparoscopic major hepatectomy (LMH) for primary hepatolithiasis have been limited to a few institutions. This retrospective study was performed to evaluate the therapeutic safety, and perioperative and long-term outcomes of LMH versus open major hepatectomy (OMH) for hepatolithiasis. From January 2012 to December 2016, 61 patients with hepatolithiasis who underwent major hepatectomy were enrolled, including 29 LMH and 32 OMH. The perioperative outcomes and postoperative complications, as well as long-term outcomes, including the stone clearance and recurrence rate, were evaluated. There was no difference of surgical procedures between the two groups. The mean operation time was (262 +/- 83) min in the LMH group and (214 +/- 66) min in the OMH group (p = 0.05). There is no difference of intra-operative bleeding (310 +/- 233) ml versus (421 +/- 359) ml (p = 0.05). In the LMH group, there were shorter time to postoperative oral intake ((1.1 +/- 0.6) days versus (3.1 +/- 1.8) days, p = 0.01) and shorter hospital stay [(7.2 +/- 2.3) days versus (11.8 +/- 5.5) days, p = 0.03] than the open group. The LMH group had comparable stone clearance rate with the OMH group during the initial surgery (82.8% vs. 84.4%, p = 0.86). LMH could be an effective and safe treatment for selected patients with hepatolithiasis, with an advantage over OMH in the field of less intra-operative blood loss, less intra-operative transfusion, less overall complications, and faster postoperative recovery.