Genomic abnormalities at 348 loci encoding genes that may contribute to lung cancer transformation and progression were assessed using array comparative genomic hybridization in 21 squamous carcinomas (SqCas) and 16 adenocarcinomas (AdCas). Hierarchical clustering showed a clear pattern of gains and losses for the SqCas, whereas the pattern for AdCas was less distinct. Cross-validated classification using a K-nearest-neighbor assigned, on average, 32 of 37 samples to their proper histological subtype. The most noticeable differences between SqCas and AdCas were gain of chromosome 3q22-q26 and loss of chromosome 3p. These occurred almost exclusively in SqCas. The region of recurrent increase is approximately 30 Mb in extent, ranging from EVI1 to TFRC. PIK3CA, the alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is in this region. The PIK3CA copy number increase was validated using fluorescence in situ hybridization to lung cancer tissue microarrays. Activity of the downstream PI3K effector protein kinase B (PKB) was higher in SqCas than in AdCas and was correlated with PIK3CA copy number (r = 0.75), suggesting that these copy number increases contribute to activation of PI3K signaling in SqCas of the lung.