Therapy with orally administered calcitriol often does not adequately control the biochemical manifestations of secondary hyperparathyroidism in uremic patients. This may be due to inadequate serum concentrations of 1.25(OH)2 vitamin D and/or to insufficient dietary calcium supplementation. In the present study, therefore, we examined the effect on parathyroid function of calcitriol and calcium carbonate, administered orally, in doses sufficient to normalize the serum 1.25(OH)2 vitamin D and calcium concentrations. After nine months of combined therapy, marked suppression of immunoreactive PTH occurred in the absence of hypercalcemia. Furthermore, prolonged therapy resulted in additional suppression of the PTH concentrations comparable in magnitude to that reported following intravenous calcitriol therapy and was associated with a mild degree of hypercalcemia similar to that which occurs with intravenous therapy. Euparathyroidism was achieved in 25% of the patients by 15 months of treatment. In conclusion, secondary hyperparathyroidism can be effectively controlled with combined oral therapy without significant hypercalcemia in selected patients with end-stage renal failure. This salutary effect may result from direct actions of 1.25(OH)2D on the parathyroid gland and/or gastrointestinal tract, or from an overall action of combined treatment to restore calcium homeostasis.