Several renal functions respond to nephron loss by a compensatory adaptation. Whether the production of 1,25(OH)2D3 also adapts to a renal mass reduction is still a matter of controversy. In the present study we have investigated in rats the influence of unilateral nephrectomy, in both the acute (48 hr) and chronic (2 to 6 weeks) state, on plasma 1,25(OH)2D3 level measured by competitive protein binding assay. In the acute state no difference in plasma 1,25(OH)2D3 level between sham-operated (SHAM) and unilateral-nephrectomized (UNI-NX) rats was found. The presence of the thyroparathyroid glands was not required for maintaining plasma 1,25(OH)2D3 at a normal level 48 hr after UNI-NX. In the chronic state in rats fed at 1.1% Ca diet, plasma 1,25(OH)2D3 (means +/- SEM) was 94 +/- 4 in SHAM and 98 +/- 8 pM in UNI-NX. In rats fed a 0.1% Ca diet it was 252 +/- 16 in SHAM and 239 +/- 20 pM in UNI-NX. Analysis of 3H-1,25(OH)2D3 plasma decay curve indicated that in UNI-NX under a high calcium diet the normalization of plasma 1,25(OH)2D3 appears to be entirely due to an increase in production, whereas under a low calcium diet part of it may also result from a moderate decrease in the elimination rate. In conclusion, this study indicates that unilateral nephrectomy does not affect the level of plasma 1,25(OH)2D3 even under a calcium restriction challenge. This compensatory adaptation appears to be independent of parathyroid hormone.