BACKGROUND MUC15, one of the hydrophilic glycoproteins that protect wet-surfaced epithelia, has been shown to be involved in tumorigenesis of various tumors. However, the mechanism of MUC15 in pancreatic cancer have not been revealed yet. Our study focused on investigating its clinical significance and function in pancreatic cancer. MATERIAL AND METHODS Using tissue microarrays and immunohistochemical staining, we evaluated MUC15 expression in 92 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). The correlations between MUC15 expression and clinicopathological variables and prognosis were analyzed. To validate our findings, we analyzed the data from an online database. We then demonstrated its function or mechanism in pancreatic cancer cell lines using transwell assay, cytotoxicity assay, cell apoptotic detection, and western blot. RESULTS The expression level of MUC15 was remarkably increased in PDAC tissues in comparison with para-cancerous tissues, and was associated with poor prognosis. Cytoplasmic MUC15 expression was identified as an independent prognostic indicator for overall survival by multivariate Cox regression analysis. Functionally, overexpressed MUC15 enhanced the migration and invasion ability in cancer cells. In vitro studies revealed that MUC15 enhanced the gemcitabine resistance of pancreatic cancer. Additionally, the regulatory mechanism of MUC15 in PDAC were correlated with ERK and AKT signaling pathways. CONCLUSIONS We performed integrated analysis and revealed that MUC15 is a good prognostic predictor for patients with PDAC. The functional experiments showed that MUC15 contributed to the malignant behaviors of pancreatic cancer in vitro.