Hypoparathyroidism is a complication of thyroidectomy that causes hyperphosphatemia primarily due to enhanced reabsorption of phosphate in the kidney resulting from decreased parathyroid hormone (PTH) secretion. Fibroblast growth factor-23 (FGF23) is a hormone-like factor that is thought to play an important role in phosphate homeostasis. However, the changes and role of FGF23 in transient hypoparathyroidism after thyroidectomy are not clear. We examined changes in serum levels of calcium, phosphate, intact PTH, 1,25-dihydroxyvitamin D, and FGF23 in 12 patients (10 women, 2 men; mean age, 51 yr) who developed transient hypoparathyroidism after thyroidectomy. Serum phosphate reached its peak level (5.9 +/- 0.5 mg/dl) approximately 4 days after development of hypoparathyroidism, and this was followed by a peak in the serum FGF23 level (71 +/- 28 ng/l). Serum levels of calcium, phosphate, and FGF23 normalized after recovery of parathyroid function. There was a significant positive correlation between serum phosphate and FGF23 levels (P<0.05). Serum FGF23 was elevated in patients with hypoparathyroidism and hyperphosphatemia and normalized along with normalized phosphate levels after recovery of parathyroid function. The peak level of phosphate always preceded that of FGF23 by several days, suggesting that elevated phosphate is a primary stimulus for release of FGF23. This homeostatic regulation of phosphate differs considerably from that of serum calcium whose change is rapidly corrected within minutes.