Background: The in-hospital mortality rate in patients undergoing percutaneous transhepatic biliary drainage (PTBD) for malignant obstructive jaundice (MOJ) is high. There are few reports on the risk factors associated with hospital death after MOJ, with most of them being retrospective analyses of single factors. Therefore, this study aimed to assess pre-, intra-, and post-procedure risk factors that were independently associated with increased in-hospital mortality in MOJ patients who underwent PTBD. Methods: One-hundred fifty-five patients with MOJ who underwent initial PTBD were included in this study. A total of 25 pre-, 4 intra-, and 6 post-procedure factors potentially related to in-hospital mortality were assessed by univariate and multivariate analyses. Results: The in-hospital mortality rate was 16.8% (26/155). Of 25 pre-procedure variables analyzed, Child-Pugh classification C, creatinine level ≥6.93 μmol/L, and quality-of-life score (≤30) were found to be significant in univariate and multivariate analyses. Increased mortality was observed in patients with 2 or more risk factors, which was significantly different from patients with no risk factors or one risk factor (P