Lung cancer including non-small cell lung carcinoma (NSCLC) represents a leading cause of cancer death in Western countries. Yet, understanding its pathobiology to improve early diagnosis and therapeutic strategies is still a major challenge of today's biomedical research. We analyzed a set of differentially regulated genes that were identified in skin cancer by a comprehensive microarray study, for their expression in NSCLC. We found that ferm domain containing protein 3 (FRMD3), a member of the protein 4.1 superfamily, is expressed in normal lung tissue but silenced in 54 out of 58 independent primary NSCLC tumours compared to patient-matched normal lung tissue. FRMD3 overexpression in different epithelial cell lines resulted in a decreased clonogenicity as measured by colony formation assay. Although cell attachment capabilities and cell proliferation rate remained unchanged, this phenotype was most likely owing to induced apoptosis. Our data identify FRMD3 as a novel putative tumour suppressor gene suggesting an important role in the origin and progression of lung cancer.