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Introduction: Water deprivation testing (H2O-dep) is usually required to distinguish between diabetes insipidus (DI) and primary polydipsia (PP) in children with polydipsia-polyuria syndrome (PP-S). The H2O-dep is challenging for children and their families. The prolonged fasting may provoke hypoglycemia and dehydration, particularly in younger children. Serum concentrations of copeptin (COP) (a surrogate marker of AVP, which is easier to measure by a robust assay), are known to increase in adults and children undergoing IV arginine (ARG) stimulation testing (ASTT). Objective: To test the hypothesis that COP levels during ASTT would differentiate between DI and PP. Methods: Serum COP responses to ARG were measured in 13 healthy short children being tested for GH deficiency (controls); and in 4 patients with PP-S. Arginine-HCl (500 mg/Kg) was infused IV from 0 to 30 min, with blood sampling at 0, 15, 30, 45, 60 min; seven of 13 controls also received clonidine PO (150 mcg/m2) at 0 min. COP was measured with a 2-site immunometric assay (BRAHMS Platform, Quest Diagnostics). Results: A-Controls. As the COP values at each time point were similar in the ARG and ARG-Clonidine controls, the data from both groups were combined. COP peaked at 45-60 min post ARG in the 13 controls. COP (Mean+SD; pMol/l)) increased from 9.7+4.3, (range 3-17) to a peak of 12.4+5.0 (range 6-21) at 60 min; Δ% increase 47+50 % (range 0-133). The peak COP values on ASTT showed no correlation with subjects’ age or peak GH response. Results B: Subjects with PP-S: On the basis of H2O-dep, MRI findings, and long-term response to desmopressin therapy, 3 of 4 children were diagnosed with central DI, and 1 with PP. Abbreviations: S[Osm], U[Osm]= serum, urine osmolality (mOsm/Kg); values obtained at the end of the H2O Dep: Subject 1. 3 y-old male, diagnosed with PP. After H2O-dep S[Osm] / U[Osm] 286 / 615. On ASTT COP (base vs. peak) 15 vs.116 pMol/l. Subject 2. 8 y-old male, diagnosed with central DI with Langerhans cell histiocytosis (LCH). MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 318/202; On ASTT COP (base vs. peak) 2 vs. 2 pMol/l. Subject 3. 2 y-old male. diagnosed with central DI, possible LCH; MRI: absent bright spot. No H2O-dep; On ASTT COP (base vs. peak) 3 vs 3 pMol/l. Subject 4. Male, 3 y-old. Diagnosed with partial DI with LCH. MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 297/569. On ASTT COP (base vs. peak) 5 vs. 6 pMol/l. Comment: In all DI patients, COP concentrations remained flat in the ASTT, at 2-3 pmol/L in 2 subjects with complete DI, and 5-6 pmol/L in 1 subject with partial DI. The latter response overlapped with that of 1 of 13 control subjects. Conclusions: These preliminary data support the hypothesis that ASTT is an easy, minimally invasive test, valuable for differentiating the etiology of PP-S in children. However, patients with partial DI may have low-normal COP responses at ASTT that overlap with values in normal children.