BACKGROUND: Children with growth hormone deficiency (GHD) have increased renal phosphorus reabsorption during rhGH therapy, Fibroblast growth factor 23 (FGF23) is a known regulator of serum phosphorus and may be responsible for this effect. METHODS: Prospective study in GHD children investigating changes in plasma C-terminal FGF23 (C-FGF23), markers of mineral metabolism, and insulin-like growth factor (IGF-1) in the first year of rhGH therapy. Normal stature children served as baseline controls. RESULTS: The two groups at baseline were similar, except GHD patients had lower baseline TmP/GFR vs. controls (p < 0.05). C-FGF23 in GHD patients trended upward at follow-up 1 (p = 0.058) and significantly increased at follow-up 2 (p = 0.0005) compared to baseline. TmP/GFR also rose at follow-up 1 (p = 0.002) and follow-up 2 (p = 0.027). The C-FGF23 rise persisted after adjusting for age, gender, sex, total calcium, and phosphorus (p < 0.01) but attenuated after adjusting for TmP/GFR or IGF-1. CONCLUSIONS: C-FGF23 rises during rhGH therapy in spite of increased Tmp/GFR, an unanticipated observation given the role of FGF23 as a phosphaturic factor. The C-FGF23 rise may be a secondary response during rhGH therapy.