Context: Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification. Objective: Our objective was to assess the relationships between sclerostin, BMD, and CP. Design: Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP. Participants: A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years. Main Outcome Measures: Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured. Results: Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm3, lumbar vBMD was 180.7/47.0/179.0 mg/cm3, coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0,and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women(P< .0001). Before and after adjusting for age, sex, bodymass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbarvertebrae vBMD(P<.0001). Sex-stratified analyses verified significant relationships in both men and women (both P<.001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P = .03). Conclusions: In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP. (J Clin Endocrinol Metab 99: 315-321, 2014).