The influence of preexisting acid-base disturbances on acute fluoride toxicity was studied in anesthetized rats. Metabolic acidosis was induced by the administration of NH4Cl and alkalosis by NaHCO3. Fluoride was infused i.v. until death occurred. One experiment involved intact animals (n = 18); another study used nephrectomized animals (n = 8). The alkalotic animals survived twice as long, tolerated higher fluoride doses (54.7 vs 29.2 mg/kg, intact; 32.5 vs 25.4 mg/kg, nephrectomized), died with higher plasma fluoride concentrations (2.60 vs 1.79 mM, intact; 3.53 vs 1.77 mM nephrectomized), and had higher systemic blood pressures, heart rates and glomerular filtration rates at any given plasma fluoride concentration. The renal excretion, renal cleareance, and fractional renal clearance (CF) of fluoride were all consistently higher in the alkalotic animals. Tissue-to-plasma fluoride concentration ratios for heart and skeletal muscle were lower in the alkalotic group, which suggested a smaller volume of distribution for fluoride in alkalosis. This was also indicated by consistently higher plasma fluoride concentrations in the alkalotic animals of the study in which all animals were nephrectomized. A preexisting metabolic alkalosis renders the animal less sensitive to the toxic effects of acutely administered fluoride. The mechanism(s) by which alkalosis protects against fluoride toxicity involves an enhanced renal fluoride clearance rate. It may also involve lower intracellular fluoride concentrations at any given extracellular fluoride level.