The mechanism of the concentrating defect of hypercalcemia is explored by examining the effect of concomitant phosphate restriction. Rats were pair fed a normal phosphorus diet, without (group 1) or with dihydrotachysterol (group 2), or a low-phosphorus diet (group 3). Hypercalcemia was comparable in groups 2 (12.1 +/- 0.6 mg/dl) and 3 (11.8 +/- 0.4 mg/dl), but serum phosphate was lower in group 3 than group 2 (3.8 +/- 0.7 vs. 7.1 +/- 1.1 mg/dl, P less than 0.005). Group 2 rats had impaired maximum urinary concentration after 24 h of fluid deprivation (2,441 +/- 450 mosmol/kg H2O, P less than 0.001) compared with group 1 (3,263 +/- 466 mosmol/kg H2O) or group 3 (3,332 +/- 515 mosmol/kg H2O) animals. Polydipsia and polyuria were found in group 2 rats only. Tubular calcium reabsorption was higher in group 2 (83.1 +/- 33.5 mg/24 h, P less than 0.001) than group 1 (47.0 +/- 26.1 mg/24 h) or group 3 (52.8 +/- 19.3 mg/24 h) animals, and medullary calcium concentration was higher in group 2 (7.57 +/- 3.08 nmol/mg dry wt, P less than 0.05) as compared to group 1 (5.04 +/- 1.37 nmol/mg dry wt) or group 3 (5.32 +/- 0.98 nmol/mg dry wt) rats. Total medullary solute concentration was significantly higher in group 3 than group 2 animals. Thus phosphate restriction prevents the defect of urinary concentrating ability of chronic hypercalcemia, probably by decreasing tubular uptake and tissue accumulation of calcium.