Background: Endoscopic Retrograde Cholangiopancreatography (ERCP), used for choledocholithiasis treatment, carries a risk of pyogenic liver abscess (PLA) due to communication between the biliary system and bowel contents. However, limited data exists on this issue. This study aims to identify the risk factors pertaining to liver abscesses following ERCP lithotomy. Methods: We conducted a retrospective case series across multiple centers to evaluate patients who developed PLA after ERCP for choledocholithiasis. Data was obtained from the Chung Gung Research Database (January 2001 to December 2018). Out of 220 enrolled patients, 195 were categorized in the endoscopic sphincterotomy (ES) group, while 25 were in the non-ES group for further analysis. Results: The non-ES group had significantly higher total bilirubin levels compared to the ES group (4.3 ± 5.8 vs 1.9 ± 2.0, p<0.001). Abscess size, location, and distribution (single or multiple) were similar between the two groups. The most common pathogens were Klebsiella pneumoniae and Escherichia coli. Pseudomonas infection was significantly less prevalent in the ES group compared to the non-ES group (3.6% vs 16.7%, p=0.007). Patients with concurrent malignancies (HR: 9.529, 95% CI: 2.667-34.048, p=0.001), elevated total bilirubin levels (HR: 1.246, 95% CI: 1.062-1.461, p=0.007), multiple abscess lesions (HR: 5.146, 95% CI: 1.777-14.903, p=0.003), and growth of enterococcus pathogens (HR: 4.518, 95% CI: 1.290-15.823, p=0.001) faced a significantly higher risk of in-hospital mortality. Conclusion: PLA incidence was higher in the ES group compared to the non-ES group following ERCP for choledocholithiasis. Attention should be given to significant risk factors, including concurrent malignancies, elevated total bilirubin levels, multiple abscess lesions, and growth of enterococcus pathogens, to reduce in-hospital mortality.