During maintenance hemodialysis in patients with chronic renal failure, acute elevations of the plasma calcium are common, although of doubtful significance. Because the mechanisms for this hypercalcemia are unclear, calcium, magnesium, and inorganic phosphate mass transfer data was collected during routine hemodialysis. While the increase in the plasma calcium did not significantly correlate with the gain of calcium from the dialysate nor with the dialysate calcium concentration, there was a significant positive correlation between the degree of hypercalcemia and the loss of body phosphate (r = 0.66, P less than 0.05, n = 15). Hemodialysis without ultrafiltration and concomitant hemoconcentration depressed the dialysis hypercalcemia by 46% (P less than 0.001). However, continuous infusion of 33.5 mmol of phosphate during a 5-hour dialysis period, which reduced the plasma phosphate fall (1.53 +/- 0.16 to 0.87 +/- 0.08 mmol/L, P less than 0.01, in the control group; compared with 1.59 +/- 0.19 to 1.35 +/- 0.11 mmol/L, not significant [NS], in the phosphate infusion group) abolished the hypercalcemia (2.38 +/- 0.07 to 2.54 +/- 0.04 mmol/L, P less than 0.01, in the control group and 2.39 +/- 0.06 to 2.41 +/- 0.04 mmol/L, NS, in the phosphate infusion group). It is suggested that during routine hemodialysis, the loss of inorganic phosphate from the body is excessive, and that phosphate as well as calcium is released from the intracellular pool in response to the rapid fall in the plasma phosphate concentration. Such rapid, repetitive, and excessive losses of phosphate, particularly from bone, may be an important cause of renal osteodystrophy.