Purpose: It has been estimated that the proportion of never-smokers among females with lung cancer is 53% worldwide and 75% in Korea. We conducted a two-stage study to identify genetic factors responsible for lung cancer susceptibility in female never-smokers. Material and Methods: In a discovery set, 2,228 potentially functional single nucleotide polymorphisms (SNPs) of 1,994 genes using the Affymetrix custom-made GeneChip, which were related to lung carcinogenesis in 181 female never-smokers with lung cancer and 179 controls. A replication study was performed on an independent cohort of 235 cases and 465 healthy controls. The functional effect of the rs10079250 was predicted through a three dimensional models of the CSF1R protein. Results: Among the 2,228 SNPs, 38 SNPs that were associated with lung cancer risk with P values lower than 0.05 in the discovery set were selected for validation. Among the 38 SNPs, the CSF1R rs10079250 was most significantly associated with lung cancer risk (in combined analysis, odds ratio=1.49, 95% confidence interval=1.16-1.92, p=0.002; under a dominant model for the variant allele). Homology-based model for CSF1R indicates that the rs10079250 lead to increase positive charge of CSF binding region of CS1FR, thereby increasing chance for binding of CSF to CSF1R. In addition, this SNP was found to increase phosphorylation of mitogen-activated protein kinase, JNK. Conclusions: Our results suggest that the CSF1R rs10079250 is functional and contribute to lung cancer susceptibility in never-smoking females.