Alterations of the human epidermal growth factor receptor 2 (HER2) protooncogene have been implicated in the carcinogenesis and prognosis of breast cancer. A polymorphism has been identified at codon 655 (ATC/isoleucine to GTC/valine [I655V]) in the transmembrane domain-coding region of this gene, which may be associated with the risk of breast cancer. In this study we aimed to determine whether the risk of breast cancer is associated with the I655V polymorphism of HER2 transmembrane domain-coding region at codon 655. The genomic DNA from breast cancer patients and control subjects underwent analysis by the polymerase chain reaction-fragment length polymorphism. We observed no overall association between HER2 genotype and breast cancer (p = 0.53). However, an elevated positive association was observed for Ile/Val+Val/Val versus Ile/Ile genotypes in women >age 60 years (p = 0.02). Further, other risk factors--namely, the body mass index and family history--were found to be risk factors for developing breast cancer (p = 0.006 and p = 0.00, respectively). In conclusion, results of this study suggest that polymorphisms of the HER2 gene may be important susceptibility biomarkers for breast cancer risk among older women.