Patients with hypercalciuria have been reported to have an exaggerated response to hydrochlorothiazide (HCTZ), implying a renal tubular defect in solute reabsorption. To determine whether this disturbance is generalized or unique to a particular pathogenetic type of hypercalciuria, we measured the increments in urinary sodium (delta Na), calcium (delta Ca), and magnesium after a 100-mg dose of oral HCTZ in 10 normal subjects and 31 patients with different types of hypercalciuric nephrolithiasis. Eleven patients with renal hypercalciuria had significantly greater delta Na (P less than 0.005) and delta Ca (P less than 0.005) than the normal subjects. Ten patients with absorptive hypercalciuria and 10 patients with fasting hypercalciuria without parathyroid stimulation had delta Na and delta Ca indistinguishable from those of normal subjects. In all groups, urinary HCTZ and basal 24-h urinary Na did not differ. The results suggest that the unique natriuretic and calciuric responses to HCTZ occur only in renal hypercalciuric patients with secondary hyperparathyroidism. The data support a renal tubular defect in renal hypercalciuric in contrast to other diagnostic categories of hypercalciuric nephrolithiasis.