Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers that likely arise from distinct patterns of genetic alterations and disruptions.1–4 Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with T-cell transcription factor (TCF)/lymphoid enhancer factor (TCF/Lef), in several human cancers including colon carcinomas.1,5–8 In this study, we observed that β-catenin was highly and uniformly expressed in a panel of non-small cell lung cancer (NSCLC) cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines, and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A, a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85%, and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.