The neuronal pentraxin II gene (NPTX2) is expressed in numerous tissues, such as the pancreas and the liver. While its activity in the brain is known to be regulated by neuronal activity, its function in the pancreas is unclear. In this study, we investigated the impact of NPTX2 on the proliferation, migration, invasion, apoptosis, and cell cycle of the pancreatic cancer cells. The expression levels of NPTX2 and their relation to the methylation level of the NPTX2 gene promoter in five pancreatic cancer cell lines were observed. The lower expression of NPTX2 in the cells was restored after the treatment of DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine). Additionally, a full-length NPTX2 cDNA was transfected into pancreatic cancer cells (PANC-1) and we obtained the stably transfected cells (PANC-1-NPTX2). The ectopic NPTX2 expression significantly promoted G0-G1 arrest and cell apoptosis, and reduced cell proliferation, migration and invasion. Notably, the pro-apoptotic gene bax expression was significantly up-regulated while pro-survival gene bcl-2 did not significantly change in the stably transfected cells. Meanwhile, Cyclin D1 was significantly down-regulated. This study suggests that NPTX2, as a tumor-suppressor, plays an anti-tumor effect on pancreatic cancer and its low expression, due to promoter hypermethylation, may play a role in the tumorigenesis of pancreatic cancer.