Resistance to the calcemic action of parathyroid extract (PTE) was shown in thyroparathyroidectomized rats after 5 hr of renal failure that was induced by either bilateral nephrectomy (NPX) or ureter ligation (UL). Studies were carried out to investigate the relationship of parathyroid resistance to the vitamin D status of the animal. Concentrations of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) and 24,25-dihydroxycholecalciferol (24,25(OH)2D3) were similar in pooled sera samples from rats either UL or sham-operated and treated with PTE. Pretreatment with oral 25-hydroxycholecalciferol or with a combination of i.v. 24,25(OH)2D3 and 1,25(OH)2D3 prior to UL failed to alter the resistance. Resistance was also present in a group in vitamin-D-deficient rats. A similar group given 1 microgram of vitamin D2 showed more parathyroid resistance than did the group not given vitamin D2. In chronic renal failure of 28 day's duration, parathyroid resistance was again demonstrated, but, in contrast to the acute renal failure models, this was partly corrected by prior 1,25(OH)2D3 administration. These studies show that parathyroid resistance is not caused by an abnormality of vitamin D metabolism in the acute renal failure model, and we suggest that the phenomenon is due to the accumulation of one or more uremic factors.