The associations between the polymorphisms in the promoter region of the V-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) gene and lung cancer risk were investigated.By direct sequencing, we first found two known polymorphisms (-536 A/G and -276 C/T). Further TaqMan assays and logistic regression analyses were performed in order to characterize the association between the -276 C/T polymorphism of ERBB3 and lung cancer risk in 425 patients with lung cancer and 411 healthy controls. To examine the potential effects of the -276 C/T polymorphism on ERBB3 transcription, luciferase reporter assays were performed in non-small cell lung cancer (NSCLC) cell lines.The -276 C/T polymorphism was associated with the risk of lung cancer in a recessive model of never-smokers. Interestingly, the T allele conferred significantly lower promoter activity by 32% and 33% than the C allele in H2009 and H358 cell lines.ERBB3 promoter polymorphisms affect ERBB3 gene expression, and contribute to genetic susceptibility to lung cancer in never-smokers.