Employing a double-masked, prospective design, bone loss at three skeletal sites has been monitored among 113 postmenopausal women participating in a placebo-controlled trial of the thiazide-like diuretic chlorthalidone for treatment of systolic hypertension. The mean duration of chlorthalidone use was 2.6 years, at doses of 12.5-25 mg/day. Compared with placebo use, chlorthalidone use was associated with significant reductions in annual bone loss rates. Non-use of chlorthalidone was associated with bone loss at the calcaneus (-0.56% per year) and the proximal radius (-0.91% per year); borderline bone gain was observed at the distal radius (+0.39%). In contrast, chlorthalidone use was associated with bone gain at the calcaneus (+0.44% per year) and the distal radius (+1.51% per year); proximal radius bone loss was significantly reduced to -0.32% per year. The average increment for three appendicular sites was +0.9% per year. These data support a causal relationship between chlorthalidone use and reduced bone loss.