The hypocalciuric response to prolonged polythiazide (PTZ) administration has been investigated in intact and thyroparathyroidectomized (TPTX) rats. After 3 control days, PTZ was given for 6 days (0.1 mg/100g body weight · 24 hp.o.). In both groups, calcium excretion fell on day 1 of PTZ and remained depressed thereafter. In the intact rats, this decrease was associated with increased sodium excretion and urine output on treatment day 1. In the TPTX rats, hypocalciuria occurred without change in sodium excretion or body weight; urine output increased on the first 2 days. Thus PTZ can reduce calcium excretion in the absence of parathyroid hormone, changes in sodium excretion, and changes in body weight (an estimate of body fluid balance with constant food intake).