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The Wnt/β-catenin pathway plays a critical role in cell proliferation and oncogenesis. To clarify the role of cytoplasmic accumulation of β-catenin in oral squamous cell carcinoma (SCC), the cDNA of a mutant form of β-catenin that lacks the entire region with the glycogen synthase kinase-3 β (GSK-3β)-specific phosphorylation site was transfected into Ca9-22 cells whose β-catenin had been expressed predominantly at the membrane, and permanent cell lines expressing aberrant β-catenin in the cytoplasm and nucleus were produced. These transfectants, C1 and C5, proliferated at similar rates to the parental Ca9-22 cells, but the cell morphology changed from polygonal to spindle-shaped and close cell-cell interaction was lost. These mutant β-catenin-expressing cells exhibited a significantly higher invasion/migration capacity than wild-type Ca9-22 cells. The transcriptional activities of this mutant β-catenin form was enhanced in these cells which could be demonstrated by an elevated level of the transcription factor T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent reporter gene activity as well as by the up-regulation of Wnt/β-catenin target gene matrix metalloproteinase (MMP)-7. Moreover, we observed the redistribution of E-cadherin, the rearrangement of actin filaments, and the elevation of active Rho family members, Cdc42 and Rac. These results suggest that aberrant cytoplasmic accumulation of β-catenin can induce Tcf/Lef-mediated transcriptional activity, up-regulate MMP-7, and induce epithelial and mesenchymal transition (EMT). This would enhance the invasion and migration of oral SCC cells.