Serum carbohydrate antigen 19-9 (CA19-9) is widely used to predict the prognosis for pancreatic ductal adenocarcinoma (PDAC). However, hyperbilirubinemia and the CA19-9 nonsecretor phenotype restrict the usage of serum CA19-9 alone. The goal of this study was to confirm the prognostic role of preoperative serum CA125 in PDAC, especially in patients with jaundice.A total of 211 patients with resected PDAC were eligible for this retrospective study, and were classified into 2 groups based on serum bilirubin levels. The prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses, and the performance of each factor in predicting overall survival (OS) and recurrence-free survival (RFS) was compared.High preoperative CA125, high TNM stage, and lymph node metastasis were independent risk predictors for OS and RFS in all patients and the 2 subgroups, but high CA19-9 was only significant when considering all patients and those with nonelevated bilirubin. Using time-dependent receiver-operating characteristic analysis, better predictive performance for OS and RFS was observed for serum CA19-9 as compared to serum CA125 in these patients.High serum CA125 can independently predict poor prognosis. Importantly, in PDAC patients with hyperbilirubinemia, preoperative serum CA125 can predict the prognosis, whereas CA19-9 cannot. Preoperative CA19-9 had better predictive performance for survival than CA125, and the performance of CA19-9 did not decline between all patients and those with nonelevated bilirubin, but was significantly affected by hyperbilirubinemia.