The growth hormone and insulin-like growth factor (IGF) axis plays an essential role in the growth and development of the mammary gland. IGF1 and IGF1 receptor (IGF1R) may also play a role in the early transformation of mammary cells. Using a nested case-control design, the association between IGF1R expression in normal breast tissue from benign biopsies and subsequent risk of breast cancer was examined in patients enrolled in the Nurses' Health Study. The tissue microarrays (TMAs) containing normal terminal duct lobular units (TDLUs) from benign breast biopsies were constructed. Immunostains for IGF1R were performed on sections cut from the TMAs. A total of 312 women had evaluable IGF1R staining in normal TDLUs; 75 subsequently developed breast cancer (cases) and 237 did not (controls). The epithelial cells in the normal TDLUs were scored for both cytoplasmic and membrane staining for IGF1R. Cytoplasmic IGF1R expression was positively associated with subsequent risk of breast cancer (OR = 2.47, 95% CI 1.41-4.33). Women having TDLU epithelial cells showed little or no membrane expression of IGF1R, but those with high levels of cytoplasmic IGF1R were at the highest breast cancer risk and were 15 times more likely to develop subsequent breast cancer when compared with women who had little or no membrane or cytoplasmic IGF1R expression in their TDLU epithelial cells (OR = 15.9, 95% CI 3.6-69.8). In this study, it was demonstrated that IGF1R expression patterns in epithelial cells of normal TDLUs in benign breast biopsies were associated with an increased risk of subsequent breast cancer. Further studies to confirm these findings are necessary.