The process of kidney stone formation depends on an imbalance between excretion of water and insoluble stone-forming salts, leading to high concentrations that supersaturate urine and inner medullary collecting duct (IMCD) fluid. For common calcium-containing stones, a critical mechanism that has been proposed for integrating water and calcium salt excretions is activation of the cell surface calcium-sensing receptor (CaSR) on the apical membranes of IMCD cells. High deliveries of calcium into the IMCD would be predicted to activate CaSR, leading to reduced membrane abundance of aquaporin-2, thereby limiting water conservation and protecting against stone formation. We have tested this hypothesis in 16 idiopathic hypercalciuric calcium stone formers and 14 matched normal men and women in the General Clinical Research Center. Subjects were fed identical diets; we collected 14 urine samples at 1-h intervals during a single study day, and one sample overnight. Hypercalciuria did not increase urine volume, so urine calcium molarity and supersaturation with respect to calcium oxalate and calcium phosphate rose proportionately to calcium excretion. Thus CaSR modulation of urine volume via IMCD CaSR activation does not appear to be an important mechanism of protection against stone formation. The overnight period, one of maximal water conservation, was a time of maximal stone risk and perhaps a target of specific clinical intervention.