SE translocation (SET) oncoprotein, an inhibitor of protein phosphatase 2A, is abnormally expressed in many cancers. In this study, SET was aberrantly upregulated in gastric cancer (GC) compared with control tissues. Clinicopathological analysis showed that SET expression was significantly correlated with pathological grade (p=0.002), lymph node stage (p=0.014), and invasive depth (p=0.022). Kaplan-Meier analysis indicated that patients with high SET expression showed poorer overall survival rates than those with low SET expression. Moreover, SET knockdown downregulated GC cell proliferation, colony formation, tumorigenesis, and metastasis. The biological effect of SET on proliferation and invasion was mediated by inhibition of protein phosphatase 2, which in turn, activated Akt. Taken together, our results suggested that SET overexpression is associated with GC progression, and it might be a potential diagnostic marker for GC, thereby a possible target for GC drug development.