Currently, there is considerable interest in characterizing cytokine responses to various types of physical activity, as these responses may partially mediate changes in cellular regulation, inflammation, and metabolism. PURPOSE: To determine responses of plasma cytokines and related markers of glucose metabolism to repeated bouts of exercise on successive days in 15 men with metabolic syndrome (age = 50 + 2 yr, BMI = 31.9 + 1.2 kg/M2, body fat = 29 + 1%, glucose = 100 + 13, triglyceride = 267 + 38, high-density lipoprotein cholesterol = 32 + 1mg/dl). METHODS: Subjects expended 350 kcals of energy by treadmill walking or jogging at 60-70% VO2peak on 4 consecutive days. Fasting blood samples were obtained each day before exercise and 24 and 72 hr after the last exercise bout. Changes in plasma volume-adjusted concentrations of glucose, insulin, non-esterified fatty acids, fetuin-A, phosphofetuin-A, adiponectin, and leptin as well as the calculated HOMA index were determined by multiple 1 x 6 repeated-measures ANOVAs. RESULTS: Significant reductions in insulin (p < 0.03) and a lower HOMA index (p<0.038) occurred after one exercise session and remained lower than baseline with exercise on successive days. Leptin concentrations decreased and stayed lower than baseline values after two exercise sessions (p < 0.0001). Plasma concentrations of glucose, non-esterified fatty acids, adiponectin, fetuin-A, and phosphofetuin-A were not significantly altered with exercise repeated on successive days. CONCLUSIONS: Our results corroborate the well-established insulin sensitizing effect of regularly-practiced exercise. Although cytokine concentrations are related directly or indirectly with metabolic dysfunction in epidemiology and tissue-specific cytokine activity may have a great effect on cellular metabolism, exercise-induced improvements in markers of insulin-mediated glucose metabolism preceded changes in plasma leptin and occurred in the absence of change in plasma cytokine concentrations.