Animal models of skeletal muscle ischemia-reperfusion injury have led to a better understanding of the pathophysiology of this condition and are necessary for the evaluation of potential therapeutics. This study presents a new, well-controlled model of ischemia-reperfusion that more accurately simulates acute arterial occlusions in humans. In rabbits, a whole hindlimb is rendered reversibly ischemic by occlusion of primary and collateral arterial inflow and then reperfused for an extended period of 48 h. Ischemic injuries are standardized by defining and controlling ischemic time, limb temperature, and the extent of collateral circulation. We have characterized this model by measuring anterior tibial and soleus muscle necrosis and edema formation in groups of animals subjected to 4 h of ischemia at either 32 or 36 degrees C, with one of two extents of collateralization and with or without muscle compartment release (fasciotomy). Our results indicate the following: (1) muscle necrosis is significantly worsened by restricting the extent of collateral blood supply or by elevating ischemic temperature; (2) anterior tibial muscle is inherently more sensitive than soleus muscle to ischemic injury; (3) fasciotomy may reduce muscle necrosis by more than 50%; and (4) the amount of edema present in muscles is an unreliable indicator of actual muscle necrosis. We conclude that this new model is a practical, well-controlled, and clinically relevant preparation useful for the investigation of ischemic muscle injury.