OBJECTIVE To determine the effects of long-term use of the thiazide diuretic chlorthalidone on serum bone-related biochemical variables in older persons. METHODS Cross-sectional comparison. METHODS Community-dwelling subjects who had participated in the Systolic Hypertension in the Elderly (SHEP) program. METHODS Sixty-six Caucasians (36 male and 30 female), age range 70 to 89 years, of whom 23 were taking a thiazide diuretic. METHODS 25-hydroxyvitamin D (25OHD), parathyroid hormone, osteocalcin, calcitonin, and serum bioavailable testosterone. RESULTS In both groups, there was a high prevalence of low 25 (OHD) levels (30%). Log 25OHD showed a significant inverse relationship to parathyroid hormone (r = .33, P < 0.05). Thiazide users had lower levels of osteocalcin (P < 0.05) and parathyroid hormone levels (P < 0.05) compared with non-thiazide users. Male thiazide users had decreased bioavailable testosterone levels compared with non-thiazide users (P < 0.05). Serum osteocalcin was significantly related to bioavailable testosterone in men not on thiazide (r = .43, P < 0.05). CONCLUSIONS Hypovitaminosis D is a common finding in older individuals with associated elevations in parathyroid hormone. Parathyroid hormone and testosterone concentration (in men) are correlated with serum osteocalcin, a measure of osteoblastic activity. Long-term thiazide use alters these relationships and produces a biochemical profile suggestive of decreased bone formation. Reduced bioavailable testosterone may also play a role in these biochemical changes.