As a member of the catenin family, little is known about the clinical significance and possible mechanism of δ-catenin expression in numerous tumours. We examined the expression of δ-catenin by immunohistochemistry in 115 cases of non-small cell lung cancer (NSCLC) (including 65 cases with follow-up records and 50 cases with paired lymph node metastasis lesions). The mRNA and protein expression of δ-catenin was also detected in 30 cases of paired lung cancer tissues and normal lung tissues by RT-PCR and western blotting, respectively. Co-immunoprecipitation was used to examine whether δ-catenin competitively bound to E-cadherin with p120ctn in lung cancer cells or not. The effects of δ-catenin on the activity of small GTPases and the biological behaviour of lung cancer cells were explored by pull-down assay, flow cytometry, MTT, and Matrigel invasive assay. The results showed that the mRNA and protein expression of δ-catenin was increased in lung cancer tissues, the positive expression rate of δ-catenin was significantly increased in adenocarcinoma, stage III-IV, paired lymph node metastasis lesions, and primary tumours with lymph node metastasis (all p < 0.05), and the postoperative survival period of patients with δ-catenin-positive expression was shorter than that of patients with δ-catenin-negative expression (p < 0.05). No competition between δ-catenin and p120ctn for binding to E-cadherin in cytoplasm was found in two lung cancer cell lines. By regulating the activity of small GTPases and changing the cell cycle, δ-catenin could promote the proliferation and invasion of lung cancer cells. We conclude that δ-catenin is an oncoprotein overexpressed in NSCLC and that increased δ-catenin expression is critical for maintenance of the malignant phenotype of lung cancer. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd