Clearance experiments were performed in female mongrel dogs, either intact or thyro-parathy-roidectomized (T-PTX), under pentobarbital anesthesia, to examine the unusual hypocalciuric property of thiazide diuretics. The relationship between calcium clearance (C_Ca) and sodium clearance (C_Na) was determined in normal dogs, C_Ca = 0.79 C_Na; constant infusion of chlorothiazide (CTZ) to provide drug concentrations in plasma of approximately 40 μg/ml modified this relationship; C_Ca = 0.30 C_Na (P < 0.001). The magnitude of the dissociating effect of CTZ on the urinary Ca/Na relationship was found to be most highly correlated with urinary drug concentration. Infusion of CTZ (1 mg/min) into one renal artery caused a unilateral decrease (25%) in C_Ca/GFR while producing a unilateral increase (80%) in C_Na/GFR. The same dose of CTZ in T-PTX dogs produced an increase in C_Na/GFR without causing a change in C_Ca/GFR. The defective response in T-PTX dogs could be ascribed to poor tubular secretion of the drug; when urinary drug concentrations were elevated in T-PTX dogs to the levels found in intact dogs (by infusing more drug), C_Ca/GFR fell to an equivalent extent. T-PTX dogs showed substantially lower renal extraction of CTZ (42%) than intact dogs (57%); PTH administration to T-PTX dogs increased extraction toward normal (49%). The defective secretion of CTZ could not be attributed to either a decreased tubular maximum or a decreased renal blood flow.