Insulin-like growth factor (IGF)-related hormones and binding proteins (IGFBP) have been implicated in cancer risk. Specifically, two recent, small prospective studies reported a significant positive association between IGF-I and ovarian cancer risk among women diagnosed before age 55 years. Therefore, we examined whether plasma concentrations of IGF-I, IGFBP-3, and IGFBP-2 were associated with risk of epithelial ovarian cancer in a nested case-control study using data from three prospective cohorts: the Nurses' Health Study (NHS), NHSII, and the Women's Health Study (WHS). The present study had 222 cases (159 from NHS/NHSII and 63 from WHS) and 599 controls (matching ratio, 1:3 for NHS/NHSII and 1:2 for WHS). Women ranged in age from 34 to 73 years (mean, 56 years). The relative risk (RR) comparing the top versus bottom quartile of IGF-I was 0.56 (95% confidence interval, 0.32-0.97; P(trend) = 0.14). The risk did not differ by age at diagnosis (comparable RR for age <55 years at diagnosis, 0.70; RR for age >/=55 years at diagnosis, 0.52). We did not observe any association between IGFBP-3, IGFBP-2, and the ratio of IGF-I to either binding protein and ovarian cancer risk. Overall, our results do not support a positive association between IGF-related proteins and ovarian cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1691-5).