Given the increasing rate of overweight and the burden of metabolic syndrome (MetS) on cardiovascular disease development, better understanding of the syndrome is of great importance. Therefore, the objectives were to examine whether interleukin-6 (IL-6) and adiponectin are associated with MetS, and whether this association is mediated by components of the MetS.During 2011-2012, 284 individuals (159 men, 53 ± 9 years, 125 women 52 ± 9 years) without cardiovascular disease, type 1 diabetes mellitus, high-grade inflammatory disease, living in the greater Athens area, Greece, participated in clinical examination. Adiponectin and IL-6 were measured in fasting plasma samples. MetS was defined according to the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria.MetS was present in 37 % (IDF) and 33 % (AHA/NHLBI) of the study population (P < 0.001). Adiponectin was inversely associated with MetS (odds ratio, 95 % confidence interval: 0.829, 0.762- 0.902 for MetS-IDF, and 0.840, 0.772- 0.914 for MetS-AHA/NHLBI). Body mass index (BMI), waist circumference, high density lipoprotein (HDL)-cholesterol, triglyceride and insulin concentration mediated the association between adiponectin and MetS-IDF (z-test, standard error, P-value: 2.898, 0.012, 0.004, for BMI; 2.732, 0.012, 0.006 for waist circumference; 2.388, 0.011, 0.017 for HDL-cholesterol; 2.163, 0.010, 0.031 for triglyceride; 2.539, 0.010, 0.011 for insulin). Similarly, BMI, waist circumference, HDL-cholesterol and insulin concentration mediated the association between adiponectin and MetS-AHA/NHLBI (z-test, standard error, P-value: 2.633, 0.011, 0.008 for BMI; 2.441, 0.011, 0.015 for waist circumference; 1.980, 0.010, 0.048 for HDL-cholesterol; 2.225, 0.009, 0.026 for insulin). However, adiponectin remained significantly associated with MetS. IL-6 was not significantly associated with MetS.MetS components, in particular obesity and lipid indices, as well as serum insulin levels, mediate the association between adiponectin and MetS as defined by both the IDF and AHA/NHLBI criteria.