To compare the safety and efficacy between open hepatectomy (OH) and laparoscopic hepatectomy (LH) in the treatment of hepatolithiasis in order to provide evidence-based medical support for the application of LH. Four hundred and two patients who underwent liver resection in our hospitals from 2002 to 2020 were selected. The patients were divided into the OH group (n=331) and the LH group (n=71) according to surgical methods. Inverse probability of treatment weighting (IPTW) was used to balance the clinical data between the two groups. The safety and efficacy were compared between the two groups. After IPTW, the overall complication rate of the LH group was 38.5%, that was lower than 69.4% of the OH group (P = 0.001). The postoperative liver failure of the LH group was 0.00%, that was lower than 3.7% of the OH group (P = 0.001). The intraoperative blood loss of the LH group was 200 ml, that was lower than 300 ml of the OH group (P = 0.032). However, there was no significant difference in median recurrence-free interval (mRFI) between the two groups. LH has specific advantages over OH in the treatment of hepatolithiasis in terms of safety. However, LH is basically similar to OH in terms of effectiveness.