The fight against lung cancer is greatly compromised by the lack of effective early detection strategies. Genomic abnormalities and specifically the amplification of chromosomal region 3q26-3qter in lung cancer represent a major signature of neoplastic transformation. Here, we address the significance of p53 homologue p63 mapping to 3q27 in lung tumorigenesis. We analyzed p63 gene copy number (CN) by fluorescence in situ hybridization and expression by immunohistochemistry in tissue microarrays of 217 non-small cell lung cancers (NSCLCs) and correlated them with survival. We additionally characterized our findings in a subset of 24 NSCLCs by reverse transcription-PCR and Western blotting. We analyzed p63 CN and protein expression in 41 preinvasive squamous lesions. The p63 genomic sequence was amplified in 88% of squamous carcinomas, in 42% of large cell carcinomas, and in 11% of adenocarcinomas of the lung. The predominant splice variant of p63 expressed was DeltaNp63alpha. Western analyses revealed DeltaNp63alpha expression in normal bronchus and squamous carcinomas but not in normal lung or in adenocarcinomas. Furthermore, p63genomic amplification and protein staining intensity associated with better survival. We found a significant increase in CN in preinvasive lesions graded severe dysplasia or higher. Our data demonstrate that there is early and frequent genomic amplification of p63 in the development of squamous carcinoma of the lung and that patients with NSCLC showing amplification and overexpression of p63 have prolonged survival. These observations suggest that p63 genomic amplification has an early role in lung tumorigenesis and deserves additional evaluation as a biomarker for lung cancer progression.