This 30-day balance study with weanling rats was designed to determine the effects of plasma fluoride and dietary calcium concentration and their interaction on the absorption, balance, and tissue concentrations of fluoride. The three major groups differed according to the total exposure and plasma concentrations of fluoride. One group received fluoride only in the diet and the other two received additional fluoride by continuous infusion from miniosmotic pumps implanted S.C. Each group was divided into two subgroups with dietary calcium concentrations of 0.4% or 1.4%. Fluoride intake with the diet did not differ among the groups. Fecal fluoride excretion was directly related to plasma fluoride concentration. The absorption and balance of dietary fluoride were inversely related to plasma fluoride concentration. These effects were greatest in the groups fed the 1.4% calcium diet. The interactions of plasma fluoride and dietary calcium on these variables were highly significant (P < 0.0001). The balance of dietary fluoride was negative in the four groups that received additional fluoride by infusion. In the two groups that received fluoride only in the diet, the plasma and bone fluoride concentrations were 41% and 59% lower, respectively, in the 1.4% dietary calcium group. The findings indicate that net fluoride secretion into the GI tract can occur when plasma fluoride concentrations and calcium intake are elevated. They suggest that elevated plasma fluoride levels and calcium intake are factors that may diminish the effect of oral fluoride treatment in osteoporotic patients.