Tumor necrosis factor-alpha (TNF-alpha) inhibitors have been used in the treatment of psoriasis, which is associated with the insulin resistance syndrome. The purpose of this study was to determine the effect of etanercept, a TNF-alpha inhibitor, on insulin secretion and insulin sensitivity in psoriatic patients with high risk factors to develop type 2 diabetes mellitus. Randomized double blind clinical trial with 2 weeks of follow-up. The allocation was done by simple randomization. The investigation was performed in 12 psoriatic patients with indication of systemic treatment and 2 or more risk factors for type 2 diabetes mellitus. Patients with infections, topical corticosteroids or salicylic acid ointments for 6 weeks before the study, diabetes, acromegaly, cancer and other systemic diseases were excluded. All subjects gave written informed consent to participate in the study and the protocol was approved by the hospital-based Ethical Committee. Etanercept was injected in a subcutaneous dose of 25 mg in 1 ml twice by week for 2 weeks or 1 ml of saline solution as placebo. Insulin secretion was estimated with the formula for the homeostasis model analysis beta-cell function index and insulin sensitivity was assessed using the euglycemic-hyperinsulinemic clamp technique. There was no significant difference in insulin secretion and insulin sensitivity with etanercept. Fasting serum insulin levels were decreased in the etanercept group (146 +/- 117-111 +/- 87 pmol/l, P = 0.04). Etanercept did not modify insulin secretion and insulin sensitivity in psoriatic patients with risk factors for type 2 diabetes mellitus.