PURPOSE: Sepsis is a possible complication of percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) for hepatolithiasis, but risk assessment tools are lacking. This study aimed to identify predictors of sepsis after PTCSL and develop a predictive nomogram. PATIENTS AND METHODS: In this nested case‒control study, the data from 298 patients who underwent 528 PTCSL sessions between 1 January 2016 and 1 July 2024 were retrospectively reviewed. All sessions demonstrating sepsis complications were included in the sepsis group. For each session in the sepsis group, two treatment date-matched sessions not demonstrating sepsis were randomly selected via a nested case‒control design. All the matched sessions were divided into training and validation sets. Least absolute shrinkage and selection operator (LASSO) analysis was conducted to preliminarily select predictors of sepsis complications. Multivariable logistic regression was performed to identify factors for constructing the nomogram. RESULTS: Sepsis was diagnosed in 46 patients (53 sessions), for an incidence of 10.69% (53 among 496 sessions). Three characteristic variables were included in the model: operation technique (odds ratio [OR]=0.170, 95% confidence interval [CI]: 0.048-0.599, P=0.006), cirrhosis (OR=3.769, 95% CI: 1.474-9.638, P=0.006), and postoperative prophylactic dexamethasone (OR=0.267, 95% CI: 0.101-0.703, P=0.008). The area under the curve (AUC) for the nomogram was 0.756 (95% CI, 0.658-0.853) in the training set and 0.762 (95% CI, 0.618-0.906) in the validation set, demonstrating relatively high discriminability. The calibration curves demonstrated the consistency between the predicted and actual values. Decision curve analysis indicated that the nomogram offers net clinical benefits. CONCLUSION: The operation technique, cirrhosis, and postoperative prophylactic dexamethasone may predict the occurrence of sepsis after PTCSL. We developed a nomogram to predict sepsis complications following PTCSL and demonstrated its relatively strong performance.