Metabolic syndrome is characterized by a constellation of multiple risk factors, such as dyslipidemia, hyperglycemia, hypertension, and abdominal obesity. Several studies have focused on the role of oxidative stress in metabolic syndrome [1][2][3][4][5][6]. For example, oxidative stress markers, such as thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, 8-hydroxy-2¢-deoxyguanosine, a biomarker of oxidative DNA damage, and oxidative modification of low-density lipoprotein, increased in the plasma of a rat model of metabolic syndrome [6]. Plasma concentrations of free fatty acids are also increased in metabolic syndrome, and might be involved in the pathogenesis of skeletal muscle insulin resistance [7,8]. Increased fatty acids resulted in cellular damage via the induction of oxidative stress [9,10]. In skeletal muscle cells, palmitate-induced mitochondrial DNA damage and cytotoxicity were caused by the overproduction of peroxynitrite [9]. Zhang et al. demonstrated that fatty acids enhanced monocyte adhesion to endothelial cells in vitro and that the process was mediated through the increased generation of reactive oxygen species and the enhanced expression of the integrin CD11b [10]. Plasma concentrations of free fatty acids are increased in metabolic syndrome, and the increased fatty acids may cause cellular damage via the induction of oxidative stress. The present study was designed to determine whether the increase in fatty acids can modify the free sulfhydryl group in position 34 of albumin (Cys34) and enhance the redox-cycling activity of the copper-albumin complex in high-fat diet-induced obese mice. The mice were fed with commercial normal diet or high-fat diet and water ad libitum for 3 months. The high-fat diet-fed mice developed obesity, hyperlipemia, and hyperglycemia. The plasma fatty acid ⁄ albumin ratio also significantly increased in high-fat diet-fed mice. The increased fatty acid ⁄ albumin ratio was associated with conformational changes in albumin and the oxidation of sulfhydryl groups. Moreover, an ascorbic acid radical, an index of redox-cycling activity of the copper-albumin complex, was detected only in the plasma from obese mice, whereas the plasma concentrations of ascorbic acid were not altered. Plasma thiobarbituric acid reactive substances were significantly increased in the high-fat diet group. These results indicate that the increased plasma fatty acids in the high-fat diet group resulted in the activated redox cycling of the copper-albumin complex and excessive lipid peroxidation.