Experimental evidence suggests that insulin and insulin-related growth factors may play a role in breast pathology through their mitogenic and anti-apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin-like growth factor-I (IGF-I), its major binding protein (IGFBP-3), the ratio IGF-I:IGFBP-3, c-peptide (a marker of insulin secretion) and the ratio c-peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, MI between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF-I, IGFBP-3 and the ratio IGF-I:IGFBP-3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c-peptide or of c-peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [CI] 1.4–6.5) and 3.3 (95% CI 1.5–7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% CI 0.7–3.0) and 1.6 (95% CI 0.8–3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women. © 2003 Wiley-Liss, Inc.