The purpose of this study was to determine whether progressive renal insufficiency alters the resistance of residual nephrons to ischemic acute renal failure. Normal rats were subjected to either sham nephrectomy (2K rats; n = 7); right nephrectomy (1K rats; n = 7); or right nephrectomy plus variable degrees of ablation (one third to three fourths) of the left kidney (less than 1K rats; n = 10). Nine additional 1K rats received varying doses of nephrotoxic antiserum (NTX rats). One week later, glomerular filtration rate was determined and then ischemic acute renal failure was induced in all remaining renal tissues (25-minute renal artery occlusion). After ischemia, glomerular filtration rate was measured for 160 minutes, renal blood flow was determined, and the kidneys were fixed by in vivo perfusion. The 2K and non-NTX 1K rats had comparable percent recoveries of glomerular filtration rate (22% +/- 5%; 23% +/- 5%) despite a 64% higher renal blood flow for the 1K group. The less than 1K rats had a significantly higher percent recovery of glomerular filtration rate (53% +/- 11%; p less than 0.01), their absolute postischemic glomerular filtration rates were comparable to those of the 2K rats, and they showed significantly less morphologic evidence of ischemic renal injury (p less than 0.01). Both NTX and non-NTX rats with renal ablation showed a strong inverse correlation between baseline glomerular filtration rate and log percent filtration rate recovery (r = -0.75, p less than 0.02; r = -0.83, p less than 0.001, respectively). The less than 1K rats (n = 6) subjected to ischemia 1 day (rather than 1 week) after renal ablation were not protected against acute renal failure (18 +/- 5%) filtration rate recovery) despite renal blood flow comparable with that in other less than 1K rats. In conclusion, progressive renal insufficiency can confer increasing protection on residual nephrons against ischemic acute renal failure once a threshold reduction in functioning renal mass is achieved (greater than 1K). The present data suggest that this protection is not a result of compensatory renal hypertrophy, increased blood flow, or increased solute excretion per nephron, but probably arises as a delayed consequence of renal insufficiency-induced alterations of the internal milieu.