Background Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study. Methods A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n???=???1622; ER???, n???=???386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results The associations between OPG and ER+ and ER??? breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER??? breast cancer (top vs. bottom tertile RR???=???1.93 [95% CI 1.24???3.02]; p trend???=???0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER??? disease did not differ by menopausal status at blood collection (p het???=???0.97), and we observed no heterogeneity by HT use at blood collection (p het?????????0.43) or age at breast cancer diagnosis (p het?????????0.30). Conclusions This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER??? breast cancer.