To examine the influence of type 2 diabetes on cytokine release from the leg at rest and during exercise, 9 male type 2 diabetics (D) and 8 age-, gender-, Vo2peak-, weight- and body mass index (BMI)-matched control subjects (C) were studied before and after 25 minutes of supine bicycle exercise at 60% Vo2peak. Blood samples were obtained from a femoral artery and vein from 1 limb, and plasma was analyzed for glucose and the cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Leg blood flow (LBF) was measured by thermodilution in the femoral vein, and net leg IL-6, TNF-α, and glucose balance were calculated as the product of LBF and femoral arteriovenous (fa-v) glucose, IL-6, and TNF-α difference. Arterial plasma glucose and IL-6 were higher (P < .05) at rest in D compared with C, but there were no differences in arterial TNF-α concentrations at rest when comparing groups. Despite measurable arterial levels of both IL-6 and TNF-α in both groups at rest, there was not net leg release of either cytokine at rest. Exercise increased (P< .05) IL-6 release and glucose uptake in both D and C, and contracting leg glucose uptake was similar when comparing D with C. While not significant, there was a trend (P = .1) for augmented exercise-induced IL-6 release in D compared with C. In contrast, exercise did not result in TNF-α release in either D or C. These data demonstrate that basal circulating TNF-α is not elevated in patients with type 2 diabetes when matched for BMI with control subjects. The results also suggest that neither type 2 diabetic nor healthy skeletal muscle releases these cytokines at rest, indicating that organs other than skeletal muscle contribute to the elevated basal IL-6 in type 2 diabetics. In contrast with IL-6, exercise does not result in the release of TNF-α from the contracting limbs of either healthy subjects or patients with type 2 diabetes.