Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of a variety of malignant tumors. To test single nucleotide polymorphisms (SNPs) and haplotypes of the EGFR in modulating the lung cancer susceptibility, we conducted a matched case-control study of 730 lung cancer patients and 730 healthy controls for examining the association in Taiwanese population. Fourteen tag SNPs distributed in EGFR were selected for genotyping and one SNP 8227G>A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer (P=0.009). Interestingly, the increase of lung cancer risk is significantly associated with never-smoking female adenocarcinoma patients harboring 8227A allele. In never-smoking female population, ORs for 8227G>A were significantly increased in adenocarcinoma subtype (adjusted odds ratio (OR) for GA genotype=1.23, 95% confidence interval (CI)=0.87-1.75; and adjusted OR for AA genotype=3.52, 95% CI=1.32-9.37, respectively). The ORs in dominant or recessive genetic model were also significantly increased in female lung adenocarcinoma subtype (adjusted OR=1.35, 95% CI=1.05-1.90; and adjusted OR=3.26, 95% CI=1.24-8.62, respectively). Haplotype analyses of 14 EGFR SNPs revealed that haplotype comprising the rare allele of 8227G>A and the common allele of the other 13 SNPs was associated with a significantly increased risk of female adenocarcinoma (OR=2.81, 95% CI=1.02-7.77). Together, our results suggest that polymorphisms or haplotypes of the EGFR play an important role in the development of lung cancer in Taiwan, particularly in never-smoking female lung adenocarcinoma.