1,25-Dihydroxyvitamin D (1,25-(OH)2D3) directly suppresses the secretion and synthesis of PTH in vivo and in cell culture. This compound has been used to treat secondary hyperparathyroidism associated with renal failure, but in some patients prolonged treatment with 1,25-(OH)2D3 results in hypercalcemia. An analogue of 1,25-(OH)2D3 with little or no calcemic activity, 22-oxacalcitriol (OCT), was recently developed. We confirmed this lack of calcemic activity by acute and chronic administration to normal rats. A single intraperitoneal injection of vehicle (propylene glycol), OCT, or 1,25-(OH)2D3 (1.0 micrograms/rat) increased calcium by 0.32, 0.30, and 1.40 mg/dl, respectively. When rats were given daily injections of vehicle or 0.5 micrograms of either 1,25-(OH)2D3 or OCT for 4 d, calcium did not change in the rats receiving vehicle or OCT, but increased from 8.4 to 11.4 mg/dl in the rats treated with 1,25-(OH)2D3. In primary cultures of bovine parathyroid cells, 10 nM OCT was as active as 10 nM 1,25-(OH)2D3, suppressing PTH release by 33%. This suppression is due, at least in part, to blocking of transcription of the PTH gene. Using a probe prepared by random prime labeling of an Msp I fragment of plasmid PTHm122, we found that a single 40-ng dose of OCT or 1,25-(OH)2D3 depressed PTH mRNA levels by 70-80% by 48 h when compared with vehicle. Thus, OCT is a very effective suppressor of PTH secretion with virtually no calcemic activity. This analogue may be a valuable tool for the treatment of secondary hyperparathyroidism.