The differential diagnosis of hyponatremia is often challenging because of its association with multiple underlying pathophysiological mechanisms, diseases, and treatment options. Several algorithms are available to guide the diagnostic approach to hyponatremia, but their diagnostic and clinical utility has never been evaluated. We aimed to assess in detail the diagnostic utility as well as the limitations of the existing approaches to hyponatremia. METHODS: Each of the 121 consecutive subjects presenting with hyponatremia (serum sodium <130 mmoL/L) underwent 3 different and independent diagnostic and therapeutic approaches: inexperienced doctor applying an established Algorithm, intensive care senior physicians acting as Senior Physician, and senior endocrinologist serving as Reference Standard. RESULTS: The overall diagnostic agreement between Algorithm and Reference Standard was 71% (respective Cohen's kappa and delta values were 0.64 and 0.70), the overall diagnostic agreement between Senior Physician and Reference Standard was 32% (0.20 and 0.19, respectively). Regarding the therapeutic consequences, the diagnostic accuracy of the Algorithm was 86% (0.70 and 0.72, respectively) and of the Senior Physician was 48% (0.01 and 0.04, respectively). In retrospect, by disregarding the patient's extracellular fluid volume and assessing the effective arterial blood volume by determination of the fractional urate excretion, the Algorithm improved its diagnostic accuracy to 95%.