The influence of cyclosporine A on renal function was investigated in unilaterally nephrectomized rats subjected to 30 or 45 min of ischemia. Acute i.v. administration of high dose CyA equivalent to 1000 mg/kg/d, did not produce a decrease in glomerular filtration or renal blood flow within 2 hours and its influence on proximal tubular pressure could be attributed to the cremophor vehicle. Chronic oral administration of 20 mg/kg/d CyA after ischemia produced no alteration in renal function after 2 or 9 days, but 40 mg/kg/d CyA lowered renal function demonstrably by 9 days. When pair-fed to eliminate CyA-induced weight loss as a cause of depressed renal function, the loss of renal function after 9 days was smaller but still evident. At this time renal cortical prostaglandin E2 and thromboxane B2 production were also reduced, but plasma renin remained unaltered because of the exclusion of volume depletion through weight loss. These kidneys showed no signs of delayed regeneration from ischemic renal injury but did show signs of tubulotoxicity, which seemed to be more apparent after longer periods of ischemia.