Purpose: Although reperfusion of acutely ischemic extremities can cause cardiopulmonary collapse and death, the humoral agent(s) released from limbs promoting this distant organ injury are not well characterized. We hypothesized that tumor necrosis factor-α (TNF-α), a cytokine that causes cardiopulmonary dysfunction in septic shock, may be released from postischemic extremities. Methods: Isolated rat hindlimbs were perfused at constant pressure with a nonrecirculating crystalloid-based buffer. After 60 or 120 minutes of normothermic ischemia, TNF activity was measured in sequential samples of venous effluent by L929 bioassay. Associated limb injury was assessed by the extent of no-reflow after reperfusion, changes in endothelial permeability to iodine 125-labeled albumin and skeletal muscle injury by uptake of technetium 99 pyrophosphate. Results: After 120 minutes of normothermic ischemia (n = 10), a 15-fold increase in TNF-α activity in venous effluent occurred, with peak activity at 1.5 minutes of reperfusion (30.6 ± 8.7 U/ml) falling to near control levels by 5 minutes. This group had a 3.3-fold increase in vascular permeability, a 2.2-fold increase in the muscle injury index and a 71.2% decline in reperfusion flow (all p < 0.05 vs control). Pretreatment of extremities with an anti-TNF-α antibody in a second group of limbs undergoing 120 minutes of ischemia (n = 10) decreased TNF activity to levels not significantly different from the nonischemic control group (n = 12). The extent of no-reflow in limbs treated with antibodies was significantly attenuated (flow 44.9% of control vs 29.8% [untreated], p < 0.05). Antibody treatment affected neither muscle injury nor vascular permeability. Conclusions: Postischemic extremities exhibited a transient, early burst of TNF release on reperfusion, which likely represented washout of TNF produced during ischemia. Suppression of TNF activity with an antibody to TNF-α resulted in a salutary increase in postischemic flow rates, suggesting that TNF may play a role in the no-reflow phenomenon.