The erbB2 (HER2/neu) gene is found amplified in tumours. A single nucleotide polymorphism at codon 655 (Ile655Val) has been studied in a number of case-control studies with respect to breast cancer risk, with conflicting results. The aim of the present study was to examine the association between this polymorphism and breast cancer risk in a prospective, predominantly Caucasian cohort of women, the Nurses' Health Study. We genotyped the Ile655Val single nucleotide polymorphism (rs1801200) in 1271 incident breast cancer cases, and 1667 controls who were selected from the Nurses' Health Study blood cohort. Controls were matched to cases on age, menopausal status, fasting status and postmenopausal hormone use at blood draw. An inverse association was observed between the Val/Val genotype and breast cancer risk (Val/Val versus Ile/Ile odds ratio=0.68, 95% confidence interval 0.47-0.98). We conclude that this polymorphism is not associated with an increase in breast cancer risk, and may in fact be associated with a modest decrease in risk.