We analyzed serum concentrations of tumor necrosis factor-alpha (TNF-alpha) for their role in insulin resistance in 12 obese men with untreated Type 2 diabetes mellitus and in 6 age-and BMI-matched obese controls. Insulin resistance was expressed using the homeostasis model assessment (HOMA-R). Six of the patients were insulin-resistant (HOMA-R>5.0), while six were not (HOMA-R</=3.0). Serum levels of TNF-alpha were higher in patients with insulin resistance (4.19+/-0.96 pg/ml) than in patients without insulin resistance (2.52+/-1.64 pg/ml) and in controls (2.03+/-1.21 pg/ml). Fasting serum concentrations of insulin and HOMA-R were higher in patients with insulin resistance (16.2+/-5.0 and 6.30+/-1.0 IU/ml, respectively) than in patients without insulin resistance (7.3+/-2.2 and 2.4+/-0.6 IU/ml) and in controls (8.0+/-2.9 and 1.8+/-0.6 IU/ml). These data suggest that high levels of serum TNF-alpha in patients with insulin resistance are related to high levels of fasting insulin and HOMA-R. We conclude that TNF-alpha may be involved in the pathogenesis of Type 2 diabetes mellitus in obese men. The importance of this investigation is that the subjects recruited in the study are BMI matched, because human obesity is associated with an increased TNF-alpha mRNA expression in adipose tissue.