Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI) ‐anchored membrane protein that is highly conserved in mammalian species. PrPc has the characteristics of adhesive molecules and is thought to play a role in cell adhesion and membrane signaling. Here we investigated the possible role of PrPc in the process of invasiveness and metastasis in gastric cancers. PrPc was found to be highly expressed in metastatic gastric cancers compared to nonmetastatic ones by immunohistochemical staining. PrPc significantly promoted the adhesive, invasive, and in vivo metastatic abilities of gastric cancer cell lines SGC7901 and MKN45. PrPc also increased promoter activity and the expression of MMP11 by activating phosphorylated ErK1/2 in gastric cancer cells. MEK inhibitor PD98059 and MMP11 antibody (Ab) significantly inhibited in vitro invasive and in vivo metastatic abilities induced by PrPc. N‐terminal fragment (amino acid 24–90) was suggested to be an indispensable region for signal transduction and invasion‐promoting function of PrPc. Taken together, the present work revealed a novel function of PrPc that the existence of N‐terminal region of PrPc could promote the invasive and metastatic abilities of gastric cancer cells at least partially through activation of MEK/ERK pathway and consequent transactivation of MMP11.—Pan, Y., Zhao, L., Liang, J., Liu, J., Shi, Y., Liu, N., Zhang, G., Jin, H., Gao, J., Xie, H., Wang, J., Liu, Z., Fan, D. Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J. 20, E1205–E1215 (2006)