The molecular mechanisms that lead to lung cancer in smokers and nonsmokers are largely unknown. This study created a composite genomic profile of the most common type of lung cancer, non-small-cell lung cancer, in smokers and nonsmokers using comparative genomic hybridization and oligonucleotide microarrays. Comparative genomic hybridization on 24 tumor specimens from 14 smokers and 10 nonsmokers with resectable (I–IIIa) non-small-cell lung cancer revealed an abnormal chromosomal copy number in 21 of 24 tumors. The number of changes in smokers was significantly higher than that in nonsmokers (P=0.005). Amplifications of chromosomes 2 (7/14; 50%) and 4 (5/14; 35.7%) were detected exclusively in smokers, whereas amplifications of chromosome 5 and allelic losses involving chromosomes 19 and 22 were equally distributed. In subsequent analyses we used Affymetrix GeneChip U95A microarrays, which allow for the analysis of approximately 11,000 full-length human genes, to analyze the gene expression patterns that correlate with these genomic changes as well as to provide a comprehensive transcriptional profile of non-small-cell lung cancer in smokers and nonsmokers. Preliminary analysis of the data revealed distinct gene expression patterns that correlated with the genomic changes. We believe that our approach, combining analysis of genomic content and alteration with analysis of gene expression, will lead to a composite genomic profile of cancer in smokers and nonsmokers, resulting in better tools for early detection, improved prediction of prognosis and discovery of new drugs to treat this devastating disease.