The hypothetical multistep model for breast carcinogenesis indicates that invasive carcinoma arises via a series of intermediate hyperplastic lesions through various grades of atypia to in situ and invasive carcinoma. Non-atypical hyperplasia [hyperplasia of usual type (HUT)] is a nonobligate precursor of breast cancer. Although its further morphological subclassification is unlikely, refining is more likely to depend on defining biological markers of risk. Having assembled a cohort of benign proliferative breast lesions of known outcome, we studied the expression of estrogen receptor-alpha (ER-alpha) and Ki-67 using morphometric image analysis as well as dual-labeled immunofluorescence in HUT foci and in surrounding normal lobules of 25 patients that progressed to breast cancer and 19 controls. Those patients that progressed to breast cancer (cases) showed significantly higher ER-alpha [median, 57.00% of cells within individual HUT foci; interquartile range (IQ), 33.48 to 67.78] and Ki-67 (median, 3.82%; IQ, 0.85 to 11.28) expression in their HUT foci compared with controls (ER-alpha median, 30.27%; IQ, 19.75 to 52.50 and Ki-67 median, 0.77%; IQ, 0.0458 to 1.72, P = 0.008 and <0.001). No significant difference in expression of dual-stained cells was found between cases and controls. Although normal lobules from cases showed higher ER-alpha expression compared with controls, this was not statistically significant. Our data point to a previously undescribed hormone-dependent pathway in this particular group of breast neoplasms and suggest the possibility of selective hormonal therapy to suppress the proliferative potential of these benign but high-risk breast lesions. The findings of this study might have important implications for improving breast cancer screening and management strategies.