MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemicrickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renaltubules. Using a specific competitive ELISA we measured a five fold increase (P=0·007) of serum ASARMpeptide(s) in human HYP patients (normal subjects 3·25 µM n=9; S.E.M. =0·51 and HYP-patients 15·74 µM, n=9; S.E.M. =3·32). A 6·23 fold increase (P=0·008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3·73 µM, S.E.M. =0·57, n=3; and hyp-mice 23·4 µM, n=3, S.E.M. =4·01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.