Epidermal growth factor (EGF), a potent mitogenic peptide, plays an important role in the development of cancers, including breast cancer. Previous studies showed that plasma EGF levels may influence the risk of cancer. In the current study, we hypothesized that genetic variants in the promoter region of EGF may influence plasma EGF levels and therefore are associated with breast cancer susceptibility. We genotyped three EGF polymorphisms (G61A, G-1380A, and A-1744G) in the promoter region by PCR-RFLP and measured plasma EGF levels using an enzyme immunoassay in a case-control study of Chinese women. We found that the mean plasma EGF levels in breast cancer patients (249.06 +/- 197.54 pg/ml) were significantly lower than those in controls (982.41 +/- 375.57 pg/ml, P < 0.001). There was a significant difference of plasma EGF levels among different genotypes carriers of the G-1380A locus in 654 controls (P = 0.007). After adjustment for age, body mass index, family history of cancer, age at menarche, and menopause status, EGF-1380AA carriers had significantly higher plasma EGF levels than -1380GG carriers did (P = 0.003). However, we did not find any significant associations between the three EGF polymorphisms (G61A, G-1380A, and A-1744G) and the risk of breast cancer. These findings indicated that plasma EGF levels served as a protective marker against breast cancer in our study and EGF G-1380A variant might be a modifier on it. Further studies are warranted to verify these findings.