Hypophysectomy abolishes the increase in serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] induced by restriction of dietary phosphorus. Administration of GH increases circulating insulin-like growth factor I levels (IGF-I) and restores, in part, the responsiveness of serum 1,25-(OH)2D to restriction of dietary phosphorus. To determine whether the GH-dependent increase in serum 1,25-(OH)2D induced by restriction of dietary phosphorus is mediated by IGF-I, we measured the serum concentration of 1,25-(OH)2D in hypophysectomized rats treated with either GH (100 micrograms/day) or recombinant human IGF-I (150 micrograms/day) and fed either a normal or low phosphorus diet for 6 days. Restriction of dietary phosphorus in sham-hypophysectomized rats increased serum 1,25-(OH)2D from 97 +/- 13 to 251 +/- 36 pg/ml, or 159%, but had no effect on serum 1,25-(OH)2D in hypophysectomized rats. Restriction of dietary phosphorus in rats receiving GH increased, (P less than 0.001) serum 1,25-(OH)2D from 52 +/- 8 to 133 +/- 18 pg/ml, or 156%. Restriction of dietary phosphorus in rats receiving IGF-I increased (P less than 0.001) serum 1,25-(OH)2D from 33 +/- 5 to 94 +/- 11 pg/ml, or 185%, an increase equivalent to that observed in animals receiving GH. For a given diet, no significant differences were seen between the serum concentrations of 1,25-(OH)2D in animals receiving GH or IGF-I. These data indicate that IGF-I can restore the increase in serum 1,25-(OH)2D induced by restriction of dietary phosphorus to the same degree as GH. This strongly suggests that the GH-dependent increase in serum 1,25-(OH)2D induced by restriction of dietary phosphorus is mediated by IGF-I.