Arterial stiffness (AS) is a complex vascular phenomenon with consequences for central hemodynamics and left-ventricular performance. Circulating biomarkers have been associated with AS; however, their value in heart failure is poorly characterized. Our aim was to evaluate the clinical and biomarker correlates of AS in the setting of heart failure with reduced ejection fraction (HFrEF). In 78 hospitalized, hemodynamically stable patients (20 women, 58 men, mean age 65.8 ± 1.41 years) with HFrEF, AS was measured using aortic pulse wave velocity (PWV). Serum OPG, RANKL, sclerostin, and DKK-1 were determined, and the relationships between the clinical variables, vascular-calcification-related biomarkers, and PWV were evaluated by correlation analysis and linear and logistic regression models. OPG and the OPG/RANKL ratio were significantly higher in the group of patients (n = 37, 47.4%) with increased PWV (>10 m/s). PWV was positively correlated with age, left-ventricular ejection fraction, and carotid intima-media thickness (cIMT), and negatively correlated with the glomerular filtration rate. OPG and cIMT were significantly associated with PWV in the logistic regression models when adjusted for hypertension, EF, and the presence of atherosclerotic manifestations. Elevated serum OPG, together with cIMT, were significantly related to increased AS in the setting of HFrEF.