The rectus femoris muscle of the rabbit is perfused by a single artery and vein and is a valuable new model for study of ischemia-reperfusion injury of skeletal muscle. The consequences of increasing duration of ischemia to the rectus femoris have been examined. Post-ischemic muscle survival (means ± SEM), as measured by Nitro blue tetrazolium (NBT) staining 24 hr after ischemia, was 90.5 ± 1.5% after 2 hr normothermic ischemia, 77.1 ± 7.7% after 3 hr, 41.8 ± 7.6% after 3 1 2 hr, and 10.7 ± 8.7% after 4 hr. Histology confirmed the NBT findings at 24 hr and showed considerable regeneration of muscle fibers 1-2 weeks after injury. The injury caused by 3 1 2 hr normothermic ischemia is the most suitable baseline for study of the effects of pharmacological agents in ischemic muscle injury. Further study of the effects of 3 1 2 hr ischemia by a quantitative Evan's blue method revealed a rapid increase in vascular permeability commencing at the start of reperfusion and lasting for 5-6 hr. Vascular labeling with saccharated ferric oxide showed widespread labeling of venules within the injured muscle and electron microscopic examination showed severe injury to both leaking and nonleaking small blood vessels. However, increased vascular permeability accounted for only a small part of the increase in weight of ischemic muscle.