The effects of reduction in energy metabolism were explored in the eel rete mirabile, an organ composed predominantly of capillaries. In vitro experiments showed that glycolysis is the major pathway of energy production in this capillary tissue, and that iodoacetate, KCN, and low PO2in combination markedly reduce its ATP generation. When in situ energy generation was inhibited by this combination during countercurrent perfusion of the arterial and venous capillaries of the rete, an approximate doubling of the intercapillary barrier permeability for human [125I]albumin, [14C]sucrose, and22Na was found. Structural damage was evident, but the intercellular junctions remained intact. The effect of cessation of flow for 30 minutes, followed by re perfusion, was then explored. Stasis alone altered the structure, chiefly of the venous capillary endothelium, but not the permeability of the intercapillary barrier. Stasis with a hypoxic medium containing the inhibitors of energy generation, followed by reperfusion with oxygenated control medium, resulted in a progressive breakdown of the intercapillary barrier, with a threefold to fourfold increase in solute (labeled albumin, sucrose, and sodium) permeability, evolving during early reperfusion, but no change for labeled water permeability. Morphologically, the endothelial cells, especially those in venous capillaries, showed substantial damage; they appeared vacuolated, then cytoplasm was extracted, and cytoplasmic and membrane debris were found in the lumen; intercellular junctions remained intact. Local pericyte detachment with interstitial edema also appeared. Thus, stasis and reperfusion amplified the effects of reduction in energy generation and hypoxia on both permeability and morphological change.