Background: Fetuin-A, a liver-secreted phosphoprotein and physiological inhibitor of insulin receptor tyrosine kinase, is associated with insulin resistance, metabolic syndrome (MetS), and an increased risk for type 2 diabetes. However, studies on the modulation of circulating levels of fetuin-A are limited. The goal of this study was to determine the effect of niacin administration on serum total- and phosphorylated fetuin-A (phosphofetuin-A) concentrations in individuals with MetS and correlate with changes in serum lipids, insulin sensitivity, and markers of inflammation. Methods: Fifteen sedentary, obese, male participants, who met the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for MetS, were treated with extended-release niacin (Niaspan) for 6 weeks. Blood samples were obtained before and after treatment with niacin. Results: Serum fetuin-A and phosphofetuin-A concentrations were decreased following niacin administration (p < 0.005). Changes in fetuin-A concentrations were correlated with changes in triglyceride (r = 0.62, p = 0.01) and C-reactive protein (CRP) concentrations (r = 0.58, p < 0.05) after niacin treatment. Changes in high-density lipoproteins (HDL)-cholesterol following niacin intervention were negatively correlated with changes in serum fetuin-A (p < 0.05) and phosphofetuin-A concentrations (p < 0.05). Serum cortisol levels were significantly elevated after niacin administration. Conclusions: Niacin treatment lowers serum total- and phosphofetuin-A concentrations in individuals with MetS, and these changes correlate with the beneficial changes in serum lipids. Because niacin is known to induce insulin resistance, these findings suggest that fetuin-A may not be a mediator of niacin-induced insulin resistance but it may blunt the insulin resistance induced by niacin by decreasing its circulating concentrations. Copyright © 2009 John Wiley & Sons, Ltd.