p202, an IFN-inducible protein, interacts with certain transcriptional activators leading to transcriptional repression. p202 expression has been associated with inhibition of cancer cell growth in vitro and in vivo. To examine a potential p202-mediated antitumor activity in pancreatic cancer, we used both ectopic and orthotopic xenograft models and demonstrated that p202 expression is associated with multiple antitumor activities that include inhibition of tumor growth, reduced tumorigenicity, prolonged survival, and remarkably, suppression of metastasis and angiogenesis. In vitro invasion assay also showed that p202-expressing pancreatic cancer cells are less invasive than those without p202 expression. That observation was supported by the findings that p202-expressing tumors showed reduced expression of angiogenic markers, such as interleukin 8 and vascular endothelial growth factor, and p202-expressing pancreatic cancer cells have reduced level of matrix metalloproteinase-2 activity, a secreted protease activity important for metastasis. Importantly, we demonstrated a treatment efficacy by using p202/SN2 liposome complex in a nude mice xenograft model, suggesting a feasibility of using the p202/SN2 liposome in future preclinical gene therapy experiments. Together, our results strongly suggest that p202 expression mediates multiple antitumor activities against pancreatic cancer and may provide a scientific basis for developing a p202-based gene therapy in pancreatic cancer treatment.