Gastric cancer (GC) is the most common cancer with a poor prognosis and the third leading cause of cancer death in the world, for which no effective therapeutic target exists. We tested the hypothesis that FAM46C might be involved in regulation of proliferation and apoptosis in GC. FAM46C was down-regulated and its expression negatively correlated with the expression of b-catenin that drives proliferation and apoptosis. Overexpression of FAM46C inhibited cell proliferation, induced G1 phase arrest and promoted apoptosis. Activation of Wnt/b-catenin signaling pathway in GC cell lines quenched the effect of FAM46C overexpression. On the other hand, FAM46C silencing attenuated DKK1-mediated inhibition of G1 phase, cessation of proliferation and induction apoptosis. Together, these data show that FAM46C shows tumor suppressor properties and such effects are mediated, at least in part, by Wnt/b-catenin in GC.