Modest weight loss causing a decrease in insulin resistance has been linked to favorable changes in the adipocyte cytokines leptin, adiponectin, and tumor necrosis factor-alpha (TNF-alpha), three emerging risk factors of cardiovascular disease. We previously observed a significant reduction in insulin resistance with weight loss in obese subjects on a low-carbohydrate diet. Based on these previous findings, we hypothesize that a low-carbohydrate diet would be more beneficial in changing leptin, TNF-alpha, and adiponectin than a conventional diet. A total of 75 severely obese (body mass index >/=35 kg/m(2)) subjects were randomized to instruction of 6 months of a low-carbohydrate diet or a conventional calorie-restricted diet. Serum levels of leptin, TNF-alpha, TNF-alpha-soluble receptor 1 (TNF-alpha SR1), and adiponectin were measured at baseline and after 6 months of dietary intervention. Subjects on low-carbohydrate diets experienced a greater decrease in leptin when compared to conventional dieters (p < 0.001). TNF-alpha increased significantly in nondiabetic subjects on conventional vs. low-carbohydrate diets (p = 0.003). Adiponectin and TNF-alpha SR1 change were not significantly different between diets. This is the first study to report the effects of dietary macronutrient alterations on serum adipocytokines in a randomized controlled trial. The greater reduction in insulin resistance and weight on a low-carbohydrate diet, in the short term, translates into greater improvement in leptin but with no significant improvements in TNF-alpha or adiponectin in patients with moderate to severe obesity after 6 months of dietary intervention.