Severe obesity increases the prevalence of the metabolic syndrome, and moderate acute weight loss with a very low-calorie diet in obese subjects with the metabolic syndrome leads to significant metabolic benefits. Adiponectin has been implicated in both the pathogenesis of obesity-related insulin resistance and increased inflammation. We analyzed the relationship of the adipocyte-derived hormone adiponectin with indices of inflammation, adiposity, and insulin resistance in obese subjects with (MS+, n = 40) and without (MS−, n = 40) the metabolic syndrome and examined the acute effects of rapid weight loss. MS+ subjects had significantly lower adiponectin (7.6 ± 0.6 vs. 10.4 ± 0.6 μg/ml; P = 0.003) and significantly higher TNF-α (3.3 ± 0.2 vs. 2.8 ± 0.3 pg/ml; P = 0.004) levels compared with MS− subjects matched for age and body mass index. Plasma adiponectin and TNF-α levels were inversely related to the number of metabolic syndrome factors in a stepwise manner. After 4–6 wk of weight loss, there was marked improvement in glucose, insulin, leptin, and triglycerides, whereas adiponectin and TNF-α concentrations did not change. Thus, increases in plasma levels of adiponectin or reductions in TNF-α are not required for marked improvements in glucose/insulin and lipid metabolism with acute weight loss.