The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)α in rodents, but an association between the TNFα system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNFα system, we measured the levels of soluble TNFα-receptor (sTNFα-R55), which has been validated as a sensitive indicator of activation of the TNFα system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNFα-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNFα-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNFα-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNFα system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNFα system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.