Other investigations, using the Hyp mouse as an animal model for the human disease X-linked hypophosphatemia (XLH), have demonstrated renal hypersensitivity to calcitonin (CT) using in vitro single renal tubule adenylate cyclase microassays. Renal hypersensitivity to CT may explain the elevated fractional excretion of phosphate (FE-P) and urinary 3'-5'-cyclic AMP (UcAMP) present in Hyp mice. This current study was designed as the in vivo counterpart to the in vitro experiments. CT dose-dependent hypocalcemia when data were constructed in normal and Hyp mice 18 hours after thyroparathyroidectomy (TPTX). Exogenous CT administered to TPTX normal mice resulted in dose-dependent hypocalcemia when data were expressed as the percent change from pretreatment. However, CT did not elicit a hypocalcemic response in TPTX Hyp mice at any dose. Only TPTX normal mice responded to CT with significant hypophosphatemia. FE-P and UcAMP were not significantly changed by CT in either genotype. In a different experiment, a large pharmacologic dose of CT was given to TPTX mice. This dose resulted in a significant but similar elevation of FE-P 1 hour after injection in both Hyp and normal TPTX mice. While UcAMP also rose significantly in both genotypes, the percent increase compared to controls was greater in Hyp mice. In summary, results from these in vivo experiments indicate that Hyp mice are not hypersensitive to physiologic doses of CT, and in fact they seem to be resistant to the hypocalcemic effect of the hormone. The greater increase in UcAMP in TPTX Hyp mice after a pharmacologic dose of CT may be the basis for the earlier in vitro results reported by others. We conclude that renal hypersensitivity to CT does not play a role in the etiology of XLH in the Hyp mouse.