OBJECTIVES: To explore the potential of serum exosomal miRNAs as novel biomarkers for pancreatic ductal adenocarcinoma (PDAC). METHODS: Serum exosomal miRNAs were screened and verified by microarray analysis and quantitative real-time PCR (qRT-PCR) in patients with PDAC and healthy controls. The correlation between the clinical characteristics of PDAC and candidate exosomal miRNAs was analyzed, and the diagnostic performance of the candidate biomarkers was evaluated. RESULTS: Serum exosomal miR-7977 and miR-451a were significantly upregulated in PDAC patients compared with healthy controls, and the levels of miR-7977 and miR-451a in serum exosomes were closely associated with the clinical stage and metastasis of PDAC patients. The area under curve (AUC) values of serum exosomal miR-7977 and miR-451a for PDAC were 0.825 and 0.804 in the training set and 0.796 and 0.830 in the validation set, respectively. A biomarker panel consisting of these two miRNAs resulted in a diagnostic power with an AUC of 0.901 in the training set and 0.918 in the validation set. CONCLUSIONS: Serum exosomal miR-7977 and miR-451a might be diagnostic biomarkers for PDAC. These two miRNAs, when combined, exhibit optimal diagnostic performance.