The effect of PTH given as a bolus on renal handling of phosphate in rats was studied by a perfusion balance study method. In vitamin D-fed rats, iv PTH as a bolus (10 USP units) elicited a phosphaturic response and an increase in urinary cAMP, whether or not the rats were thyroparathyroidectomized. When given to thyroparathyroidectomized rats receiving continuous infusion of PTH (2.5 USP units/h) for 16 h, PTH led to a paradoxical decline of phosphate clearance in spite of an increase in urinary cAMP. Vitamin D-deficient intact rats also showed this paradoxical response. Vitamin D-deficient thyroparathyroidectomized rats showed an ordinary phosphaturic response. When PTH had been supplied continuously (2.5 USP units/h) to these rats, the PTH bolus again produced the paradoxical response. Phosphate supplementation did not restore the phosphaturic response. (Bu)2cAMP infusion reproduced the paradoxical effect in vitamin D-fed, thyroparathyroidectomized rats receiving continuous infusion of PTH. These data indicate that a long-lasting excess of circulating PTH alters the nature of the response of the kidney to an iv bolus of PTH, so that PTH leads to a paradoxical decline of phosphate clearance, and that the mechanism responsible for the paradox may lie in a step (or steps) subsequent to cAMP production.