||Early prospective studies suggested circulating insulin-like growth factor (IGF)-I was positively associated with risk of premenopausal, but not postmenopausal, breast cancer; however, a recent, large analysis reported a statistically significant positive association with postmenopausal disease. Therefore, we conducted a large study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to assess the association between circulating IGF-I and IGF binding protein (IGFBP)-3 levels and subsequent postmenopausal breast cancer risk. We included 389 breast cancer cases and 470 controls, aged 55-74, not using exogenous hormones at blood draw, and matched by age at and date of serum collection. Mean follow-up was 8.5 years; mean time between serum collection and diagnosis was 4.0 years. We used Cox proportional hazards regression models to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs). Multivariate HRs for IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3, comparing the highest quintile to the lowest, were 1.28 (95% CI, 0.67-2.44), 1.12 (95% 0.55-2.27), and 1.25 (95% 0.72-2.15), respectively. Multivariate HRs per one quintile increase were 1.07 (95% 0.92-1.25) for IGF-I, 1.01 (95% 0.86-1.18) for IGFBP-3, and 1.10 (95% 0.98-1.24) for the molar ratio. These models included accepted breast cancer risk factors and height, along with baseline BMI and serum estradiol, both of which increased the risk associated with IGF-I and the molar ratio. IGF-I and the IGF-I/IGFBP-3 molar ratio were positively, although not statistically significantly, associated with postmenopausal breast cancer risk. Further research should emphasize larger studies, including pooled analyses, analyses by cancer subtype, improved exposure assessment, and possible mechanisms.