The LD50 for fluoride was elevated from less than 60 mg F/kg body weight to 172 mg F/kg when magnesium (as MgCl2), equivalent to 3 times that of F, was administered by gavage 30 min after the F dose. A dose of 30 mg F/kg elevated the mean steady state of F in serum nearly 1.5-fold and in femoral bone nearly 2-fold when administered with or without the subsequent Mg dose and observed 24 h after the electrolyte dosages. Also, in 24-hour urine the mean F excretion was highest in the F and FMg groups. The total F excretion (fecal + urinary) was elevated 8- and 10-fold when fluoride was administered with or without magnesium, as compared to control levels. Magnesium administration with fluoride did not significantly modify the above mean values of the group given fluoride alone. This suggests that interference with the absorption of fluoride was not the primary protective function of magnesium against the acute toxicity of fluoride. Additional experiments, conducted to further clarify the toxic mechanism of fluoride and the protective mechanism of magnesium, resulted in the following findings: An intraperitoneal dose of 20 mg F/kg elevated fluoride concentration in serum in 1 h about 20 times compared to the controls. Magnesium injected simultaneously with fluoride did not modify the effect of fluoride alone. No significant changes were found in the concentrations of K, Mg, Na or Ca of the lung, skeletal muscle, kidney or liver after these injections except for some trend of elevation of Ca in the heart. However, after a dose of 30 mg F/kg i.p., the heart Ca/Mg mole ratio was elevated within 1 h from 0.037 to 0.194, while all of these rats died within 1 h after the injections. When magnesium, equivalent to 3 times the amount of fluoride was injected, this mole ratio was only 0.095, and all rats in this group survived over 1 h. These results suggest that the lethality of fluoride may be dominantly mediated by the elevated Ca (Ca/Mg ratio) in the heart muscle and that this is correctable by Mg.