The study was designed to compare the effectiveness of two-step percutaneous transhepatic choledochoscopic lithotripsy (T-PTCSL) with laparoscopic anatomical hepatectomy combined with choledocholithotomy (LAHC) for patients with hepatolithiasis. From January 2020 to September 2023, 98 patients who underwent LAHC (n = 40) or T-PTCSL (n = 58) for hepatolithiasis in our hospital were included in this study. Their perioperative and long-term outcomes were analyzed. There was no statistical difference between the two groups in stone clearance rates (90.0% vs. 84.5%, P = 0.429) and postoperative complication rates (35.0% vs. 22.4%, P = 0.170). The T-PTCSL group had significantly shorter operative time, postoperative hospitalization, and intake time (all P <
0.001). Postoperative biochemical indices showed lower ALB, ALT, AST, and WBC in the T-PTCSL group compared to the LAHC group (all P <
0.05). Multivariate logistic regression indicated age as an independent risk factor for stone clearance (OR = 0.94, 95% CI = 0.89-0.99, P = 0.049). Subgroup analysis showed no significant impact of gender and type of stone distribution on stone clearance (all P >
0.05). The KM curve analysis revealed no significant difference in stone recurrence between the groups (log-rank P = 0.925). Hemoglobin concentration was significantly associated with time-to-stone recurrence (TR = 1.02, 95% CI = 1.01-1.04, P <
0.05) in the multivariate Accelerated Failure Time Model. T-PTCSL may be an alternative option to LAHC. Compared with LAHC, T-PTCSL offers favorable postoperative recovery and less surgical injury for patients with hepatolithiasis, as well as equivalent effectiveness of stone clearance and recurrence.