Low-grade inflammation is linked to metabolic syndrome and obesity. We studied the effects of weight loss and dietary composition on serum concentrations of biomarkers of inflammation and adipokines.Men and women (n=181) aged 30-65 years with a body mass index (BMI) of 28-40 kg/m(2) (28-35 kg/m(2) for women) and one or more components of metabolic syndrome were randomized to follow one of two hypocaloric diets, a low-fat or low-glycemic-load diet for 3 months. Blood samples were taken pre- and postintervention. Serum concentrations of interleukin-6 (IL-6), tumor necrosis factorα (TNF-α), plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), and adipokines (leptin, resistin, and adiponectin) were analyzed using multiplexed microsphere immunoassays.Weight loss was not different in the low-fat (4.4%±3.8%) and low-glycemic-load (4.9%±3.2%) groups. Concentrations of IL-6, TNF-α, PAI-1, and leptin were significantly reduced in both dietary groups with no between-group differences, whereas MCP-1 and adiponectin concentrations did not change. Subjects with full metabolic syndrome (three or more components; n=109) experienced greater weight loss than subjects (n=72) with one to two components and greater reduction in leptin [7.08 (95% confidence interval 5.19, 8.97) vs. 3.46 (0.91, 6.00) ng/mL; p=0.02] and a tendency to greater reduction in TNF-α (1.00 [0.60, 1.44] vs 0.40 [0.02, 0.78] pg/mL; p=0.05).Hypocaloric diets improved inflammatory biomarkers and adipokines independently of dietary composition. The response tended to be greater in subjects with three or more components of metabolic syndrome than their counterparts with one to two components.