Background: SNPs may modulate individual susceptibility to carcinogens. We used GWAS to identify SNPs associated with individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco induced NSCLC. We hypothesized that selection of extreme phenotypes would enrich the frequencies of alleles that contribute to the trait, thus increasing the power to identify them. Methods: From an identification cohort (n=3631) we selected caucasian heavy smokers that either developed NSCLC at an early age (cancer cohort) or that did not present NSCLC at an advanced age (cancer free cohort). We analyzed their genomic DNA using the array Illumina HumanOmni 2.5 Quad that includes over 2 million powerful markers selected from the 1000 Genomes Project, targeting genetic variation down to 1% minor allele frequency. Results: 96 patients (48 per cohort) were selected. Mean age for the cancer and cancer free cohorts was 49 (range 38-55) and 76 years (72-84). Mean tobacco consumption was 41 (range 18-99) and 68 pack-years (40-120). GWAS identified 8 SNPs differentially expressed by logistic regression and 54 SNP by Fisher´s test (p<10^-5). Odds-ratio ranged between 0.08-0.29 for protective SNP and 3.4-11.2 for SNP that increased NSCLC risk. Candidate SNPs were located within or in adjacent regions of genes related to: a) oncogenic and tumor-suppressor pathways: CSMD1, FOXF1, MSX2, SOX11; b) tobacco induced NSCLC: ABCB5; c) regulation of transcription: DROSHA, HDAC9, KIAA0947; d) regulators of inflammation through the NF-kappa pathway: pellino E3, TRIM9; e) previously linked to carcinogenesis and cancer prognosis: ABHD6, GRIK1, RAB40B, SCN1A, SLC24A2, SLC25A26, ZFYVE26; and f) not previously linked to cancer: ACER3, AP000946.2, ATP10A, ATP10D, CNTN5, CYYR1, LINC00572, PDE10A, RP11-115D19.1, RP11-202D1.3, RP11-521E5.1, SYTL5, ZPBP. Conclusions: We identified candidate SNPs potentially associated with the risk of developing tobacco induced NSCLC in individuals with extreme phenotypes. Validation of the most significant SNPs in an independent set of individuals with similar phenotypes is ongoing.