The molecular regulation of the growth of pancreatic carcinoma (PCC) is complicated and not defined yet. Here we show that the cysteine-rich protein 61 (Cyr61) levels were significantly higher in PCC than in the adjacent nontumor tissues from the same human patient. Overexpression of Cyr61 enhanced the proliferation of PCC cells, while inhibition of Cyr61 decreased the proliferation of PCC cells. Further analysis showed that Cyr61 seemed to activate phosphatidylinositol 3-kinase (PI3K) but not extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway in PCC cells, which subsequently induced nuclear exclusion of a major cell cycle inhibitor, p27, to increase cell proliferation. Taken together, these findings reveal the molecular basis underlying Cyr61-regulated PCC proliferation, suggest a potential role of Cyr61 in PCC growth, and highlight Cyr61 as a novel target for PCC therapy.