Allelic variants of the tumor necrosis factor-α (TNF-α) gene seem to contribute to insulin resistance increasing the transcription rate of TNF-α. The TNF-α −863A allele is associated with a lower expression of TNF-α gene and less secretion of the cytokine. To investigate whether an abnormal TNF-α system regulation may contribute to early impairment of insulin action in first-degree relatives of patients with type 2 diabetes mellitus (DM), we studied the TNF-α -863C/A polymorphism and the soluble fraction of TNF-α receptor-2 (sTNFR2) concentration in these subjects in comparison to a control group. A total of 52% of subjects in the relatives’ group showed an abnormal oral glucose tolerance (either as impaired glucose tolerance [IGT] or diabetes) and had more features of the insulin resistance syndrome, despite showing similar body composition as controls. The plasma concentration of the sTNFR2 was higher and insulin sensitivity (%S) was lower in the relatives’ group than in the controls. Likewise, the TNF-α −863A allele was more commonly detected in the control group (10 of 41) than in the relative’s group (2 of 36, P = .029). In a multivariate linear regression analysis, neither TNF-α −863A allele nor sTNFR2 independently determined %S. Only body mass index (BMI) and the presence of a positive family history of DM were independent determinants of insulin resistance. In summary, our study showed a lower rate of TNF-α −863A allele and higher concentrations of sTNFR2 in first-degree relatives of DM subjects. These findings could be included among the genetic, metabolic, and clinical heterogeneity that characterizes the pathophysiology of DM. The presence of abnormalities in the TNF-α pathway could predispose to the development of DM in subjects at risk for the disease.