Osteoprotegerin (OPG), a member of tumor necrosis factor receptor superfamily, has been implicated in vascular disease. We investigated the association of serum OPG with the ankle-brachial index (ABI) and urine albumin:creatinine ratio (UACR), in a bi-ethnic cohort of 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic whites (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of OPG were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and peripheral arterial disease (PAD) defined as ABI<0.90. UACR was expressed as mg albumin/gm creatinine. Multivariable regression analysis using generalized estimating equations (GEE) were performed to assess whether serum OPG levels were associated with ABI and UACR. After adjustment for conventional risk factors (age, sex, diabetes, waist circumference, history of smoking, total and HDL cholesterol, hypertension), prior history of myocardial infarction or stroke, and medication (renin-angiotensin-aldosterone system inhibitors, statins, aspirin, estrogen) use, higher OPG levels were significantly associated with lower ABI and higher UACR in African-Americans (P=0.001 and P<0.0001, respectively) and non-Hispanic whites (P=0.017 and P=0.002, respectively); the association remained significant after further adjustment for plasma C-reactive protein (CRP) in both ethnic groups. In multivariable logistic regression analysis, higher OPG levels were associated with PAD in African-Americans, independent of the covariates listed above (P=0.026); the association remained significant after additional adjustment for plasma CRP (P=0.047). In non-Hispanic whites, the association of higher OPG levels with PAD was of borderline significance after adjustment for the relevant covariates (P=0.106). We conclude that higher OPG levels are associated with lower ABI and higher UACR, independent of conventional risk factors and plasma CRP.