There has been controversy regarding the initial pathogenic events involved with the hyperparathyroidism of chronic renal failure (CRF). Low serum levels of 1,25-dihydroxyvitamin D in uremic patients are postulated by some as having a role in permitting higher parathyroid hormone (PTH) secretion. However, recent animal and in vitro studies strongly suggest that phosphate has a direct effect on parathyroid cells to enhance PTH secretion. To evaluate the relationships among serum phosphate, calcium, PTH, and 1,25-dihydroxyvitamin D in uremic humans, we performed a cross-sectional analysis of 84 patients with varying levels of CRF. Using stepwise regression analysis after adjusting for multiple comparisons, we found that serum phosphate correlated directly with serum PTH (r = 0.62, P < 0.01) in patients with mild to moderate CRF (creatinine < or = 3.0 mg/dL), independent of serum calcium and 1,25-dihydroxyvitamin D levels. In patients with more severe renal failure (creatinine > 3.0 mg/dL), only the serum calcium correlated with serum PTH (r = -0.47, P < 0.01). While serum 1 ,25-dihydroxyvitamin D showed no correlations with PTH, phosphate, or calcium at any stage of renal failure, the mean 1,25-dihydroxyvitamin D level in patients with mild CRF was lower than that in age-matched controls (24 +/- 3 pg/mL v 37 +/- 2 pg/mL; P < 0.01), suggesting that low 1,25-dihydroxyvitamin D was permissive for enhanced PTH secretion. These data demonstrate an independent association of serum phosphate with PTH in patients with CRF and suggest that phosphate may directly enhance PTH secretion in this setting. This study supports recent animal studies showing a direct parathyroid cell effect of phosphate on PTH secretion.