The effect of hypoxia on the morphology of the proximal tubule was examined in isolated rat kidneys perfused with Krebs-albumin medium, gassed with 95% N2/5% CO2 for 45, 90 and 190 min. The major findings were heterogeneity of types of cell injury and definable topographical zones of protection from damage. The characteristic injury in S1 and S2 was that of mitochondrial swelling and brush border alterations that progressed to complete disorganization of this zone. S3 manifested two distinct lesions, one characterized by cell swelling and the other by tubular epithelial fragmentation. Protection from these injuries was seen in tubules located in periarterial zones, apparently due to gradients of oxygenation. The same types of injury but without zones of protection were seen after perfusion with cyanide (10 mM) in oxygenated medium. A "reflow" period of oxygenated perfusion did not alter the fundamental character of these lesions but affected tubules showed progression of damage while there was preservation of tubules in periarterial areas. Thus the responses of the proximal tubule to hypoxic injury depends both on segment type (S1, S2 versus S3) and on tubular location in relation to O2 availability. Additional factors appear to determine the type of response in S3 tubules.