We evaluated parathyroid function in 158 normal subjects, aged 23-85 yr. Calcium, phosphorus, creatinine, and cAMP were measured in blood and urine in the fasting state and after a 1-g oral calcium challenge. Serum immunoreactive PTH (iPTH) was measured with a goat antiserum developed against human PTH, using (43Tyr) human PTH-(44-68) as tracer and standards. With age, a decrease in total serum Ca (r = -0.14; P less than 0.05) was attributable to a fall in serum albumin (r = -0.40; P less than 0.001). Creatinine clearance fell from 124 ml/min at age 20 yr to 61 ml/min at age 80 yr (r = -0.44; P less than 0.001). iPTH rose with age in men (r = 0.21; P less than 0.05) and women (r = 0.31; P less than 0.001) from 29 pg/ml at age 20 yr to 48 pg/ml at 80 yr. iPTH was also correlated with creatinine clearance (r = -0.32; P less than 0.001. When renal function was controlled in the analysis, the regression of iPTH with age was no longer significant. Other significant correlations with age include a decrease in renal phosphorus reabsorption (r = -0.17; P less than 0.05) and an increase in urinary nephrogenous cAMP excretion (r = 0.34; P less than 0.01). The rise in nephrogenous cAMP was not accompanied by a change in total urinary cAMP, since plasma, and therefore filtered, cAMP decreased with age. Basal calcium excretion was stable, but the calciuric response to oral calcium decreased (r = -0.27; P less than 0.01). We conclude that loss of renal function is the major cause of rising iPTH levels with age.