Background: Early biliary infection (EBI) is a significant and prevalent complication following percutaneous transhepatic biliary stenting, especially in cases involving the use of 125I particle stents for malignant biliary obstruction (MBO). Objectives: This study aims to uncover potential risk factors contributing to EBI post-implantation in this patient group. Patients and Methods: In this retrospective study, a total of 231 patients who underwent 125I particle stent implantation between January 2014 and December 2020 were included. Screening based on inclusion/exclusion criteria identified a total of 178 patients (115 males and 63 females, aged 32 - 83 years). Early biliary infection occurrence was monitored within the first 30 days following the stent implantation, when infectious complications are most prevalent. We analyzed baseline characteristics and perioperative parameters of patients, comparing those who developed EBI with those who did not. Multivariate logistic regression was employed to identify significant risk factors for EBI. Results: Out of the 178 patients, 35 (19.7%) developed EBI within 30 days post-implantation. Every EBI case was accompanied by a positive bile culture. Notably, patients with EBI more frequently had diabetes [odds ratio (OR), 3.329; 95% confidence interval (CI), 1.129 - 9.819; regression coefficient (B) = 1.203; P = 0.029], gallstones in the gallbladder or bile ducts (OR, 3.459; 95% CI, 1.060 - 11.283; B = 1.241; P = 0.040), higher level of biliary obstruction (OR, 3.008; 95% CI, 1.243 - 7.280; B = 1.101; P = 0.015), intraoperative biliary bleeding (OR, 5.416; 95% CI, 1.569 - 18.696; B = 1.689; P = 0.008), and postoperative intrahepatic pneumobilia (OR, 2.655; 95% CI, 1.108 - 6.362; B = 0.976; P = 0.029) compared to those without EBI. These factors were positively correlated with EBI development post-implantation. Conversely, the duration from percutaneous transhepatic biliary drainage (PTBD) to 125I stent implantation was longer in patients without EBI (OR, 0.966; 95% CI, 0.940 - 0.992; B = - 0.035; P = 0.012), suggesting a negative association with EBI occurrence. Conclusion: This study identifies diabetes, gallstones in the gallbladder or bile ducts, high-level obstruction, intraoperative biliary bleeding, and postoperative intrahepatic pneumobilia as significant risk factors for EBI. Additionally, a longer interval from PTBD to 125I stent implantation emerges as a protective factor against EBI in patients with MBO undergoing 125I particle stent implantation. These risk factors can offer guidance to minimize post-125I particle stent implantation biliary infection, thereby shortening hospitalization for affected patients.