Glycerol induced acute renal failure (ARF) is known to attenuate subsequent mercuric chloride nephrotoxicity. This protection was evaluated in rats. Glycerol induced varying degrees of renal insufficiency. After 14 days, when serum creatinine (SCr) creatinine clearance (CCr) and fractional excretion of sodium (FENa) had returned to baseline, injection of mercuric chloride caused significantly milder renal insufficiency in recovered rats than in controls (SCr 356 +/- 46 vs. 475 +/- 19 mumol/L; CCr 0.12 +/- 0.02 vs. 0.02 +/- 0.02 mL/min, p < .05; and mortality 0 vs. 45%, respectively, p < .01). A striking finding was that the degree of renal insufficiency induced by mercuric chloride correlated inversely with the degree of renal insufficiency previously induced by glycerol (r = -0.496, p < .05 for SCr and CCr), but there was no correlation with other measures of previous renal function such as urine volume, sodium excretion, or FENa. Glycerol induced ARF also attenuated the renal toxicity of mercuric chloride injected 4 days after glycerol, before full recovery of renal function. The decrements in renal function after the two insults were also inversely related (r = -0.76, p < .01). A third renal insult with a second mercuric chloride injection after three weeks was still attenuated. However, after the third insult, there was no longer an inverse or any statistical relationship with previous measurements of renal function. Histopathology revealed a good correlation between peak Scr after glycerol, and percentage of tubules undergoing re-generation 14 days later (r = 0.97, p < .01). There was an inverse correlation between Scr after mercuric chloride (administered 14 days after glycerol) and percentage of tubular regeneration seen two days later (r = -0.79, p < .05). The correlations of SCr and CCr with regeneration was greater than the correlations with tubular necrosis, suggesting that the regenerative process is involved in the protection from repeated renal insults. In conclusion, glycerol-induced ARF attenuates subsequent mercuric chloride renal insult. The attenuation correlates directly with the initial glycerol-induced damage, so that the more severe the initial renal insufficiency, the milder the renal insufficiency following subsequent mercuric chloride. This protection can be seen as early as 4 days and also 14 days after previous renal insult. The degree of renal tubular regeneration correlates well with the protection seen, and probably plays a role in acquired renal resistance to repeated insults.