Background: Treatment of patients with hyponatremia varies widely. Thus, readily available and reliable parameters are needed to guide the appropriate treatment strategy. This study was designed to determine the diagnostic potential of copeptin, the C-terminal part of the vasopressin precursor peptide, as a surrogate of AVP secretion, and to examine its value in the differential diagnosis of hyponatremia. Methods: In this prospective observational study, 106 consecutive hyponatremic patients (serum sodium Results: Four patients (4%) were diagnosed as primary polydipsia, 9 patients (8%) as diuretic-induced hyponatremia, 42 patients as SIAD (40%), 29 patients as hypovolemic hyponatremia (27%), and 22 patients as hypervolemic hyponatremia (21%). In controls, a close correlation between plasma copeptin and serum sodium (r=0.78, Pr=0.57, P=0.001) was observed. In hyponatremic patients, plasma copeptin levels were significantly higher in hypo- and hypervolemic hyponatremia compared to SIAD (PPPConclusion: In hyponatremic patients, plasma copeptin reliably reflects AVP secretion. In these patients, the [Copeptin/U-Na] ratio allows to distinguish accurately between volume-depleted and normovolemic disorders, while the combined information on plasma copeptin and urine osmolality confers a high diagnostic accuracy in the diagnosis of polydipsia.