Increased ubiquitin-specific protease 5 (USP5) has been associated with tumorigenesis of malignancy including glioblastoma, melanoma and hepatocellular carcinoma. However, the role of USP5 in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC) has not been studied yet. In this study, we demonstrated that USP5 was significantly upregulated in a panel of PDAC cell lines and correlated with FoxM1 protein expression. USP5 knockdown inhibited proliferation of PANC-1 and SW1990, two PDAC cell lines. In the mouse xenografted pancreatic tumor model, suppression of USP5 significantly decreased tumor growth, correlated with down regulation of FoxM1. Additionally, we found that overexpression of USP5 stabilized the FoxM1 protein in PDAC cells. Overexpression of USP5 extended the half-life of FoxM1. Knockdown of USP5 in PANC-1 cells decreased FoxM1 protein level while the proteasome inhibitor MG-132 treatment restored FoxM1 expression. We also found that endogenous USP5 was coimmunoprecipitated with an endogenous FoxM1 from PANC-1 cells while FoxM1 was also coimmunoprecipitated with USP5. Furthermore, we also confirmed that USP5 regulated proliferation of PDAC via FoxM1 by rescuing the inhibitory effect of USP5 knockdown with ectopic expression of FoxM1 in USP5-depleted cells. Taken together, our study demonstrates that USP5 plays a critical role in tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein, and provides a rationale for USP5 being a potential therapeutic approach against PDAC.