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Objectives: Polyuria-polydipsia syndrome (PPS) is a common presentation in children but the differential diagnosis rests on burdensome water deprivation tests. The aims of this study were to determine a copeptin threshold to distinguish patients with central diabetes insipidus from those with primary polydipsia and to estimate the normal range of copeptin concentrations in children., Design: Single-centre retrospective descriptive study., Patients: Two hundred and seventy-eight children aged 2 months to 18 years who consulted for PPS (N = 40) or other reasons (control group, N = 238) at La Timone University Hospital in Marseille, France, between April 2015 and September 2019 and had a copeptin assay., Measurements: Ultrasensitive copeptin assays on blood samples., Results: Among the children with PPS, the mean copeptin concentrations were 1.72, 55.2 and 15.7 pmol/l in those with central diabetes insipidus (N = 21), nephrogenic diabetes insipidus (N = 3), and primary polydipsia (N = 16), respectively. Copeptin levels lower than 3.53 pmol/l were diagnostic of central diabetes insipidus with 100% sensitivity and 87.4% specificity (p < .001). The 5th-95th copeptin percentile range in the control group was 2.53-21.03 pmol/L. Copeptin levels were significantly higher in boys than in girls but there was no association with age, pubertal stage, body mass index, or the reason for consulting., Conclusions: Our results indicate copeptin assays may be valuable in the differential diagnosis of PPS in children. Larger prospective studies are required to establish their accuracy in everyday clinical practice., (© 2021 John Wiley & Sons Ltd.)