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Mutations and variants in the EGFR (epidermal growth factor receptor) gene have been demonstrated to be associated occurrence, metastasis and prognosis of different types of tumors including lung cancer.Thus, this study is to investigate whether the intron 1(CA)n repeats,-216G/T and R497K, the functional polymorphisms in the EGFR promoter are able to induce EGFR activation and overexpression are associated with pleural metastasis of lung adenocarcinoma.The study subjects were comprised of 424 patients with primary lung adenocarcinoma and 432 matched cases with pleural metastasis.The (CA)n repeat genotypes were determined in all subjects by Capilary Electrophoresis(CE), PCR amplification and direct DNA sequencing; R497K and-216G/T genotypes were determined in all subjects by PCR amplification and direct DNA sequencing, and EGFR expression was also evaluated by immunohistochemical staining in the primary tumor tissues with different-216G/T, R497K and (CA)n repeats genotypes backgrounds.Our results showed that there were significant differences in the genotype and allele distribution of-216G/T, R497K and intron 1(CA)n repeats polymorphisms of the EGFR gene between pleural metastasis group and non-metastasis group.The-216T allele, Arg allele and shorter (CA)n repeats (<17)had significantly increased risks of pleural metastasis compared with the-216G allele, Lys allele and longer (CA)n repeats (≥17) respectively.Further more, the expression of EGFR was higher in patients with genotypes of-216T/T or-216G/T, Arg/Arg and the shorter (CA)n repeats (<17) than that in patients with genotypes of-216G/G, Arg/Lys or Lys/Lys and longer (CA)n repeats (≥17)respectively.These results collectively indicate that the-216G/T, R497K and intron 1(CA)n repeats polymorphisms were associated with the risk of the pleural metastasis of lung adenocarcinoma and that this effect may be associated with-216G/T, R497K and intron 1(CA)n repeats induced overexpression of the EGFR protein.