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Background Hyponatraemia is common and its differential diagnosis and consequent therapy management is challenging. The differential diagnosis is mainly based on the routine clinical assessment of volume status, which is often misleading. Mid-regional pro-atrial natriuretic peptide ( MR-pro ANP) is associated with extracellular and cardiac fluid volume. Methods A total of 227 consecutive patients admitted to the emergency department with profound hypo-osmolar hyponatraemia (Na < 125 mmol L−1) were included in this prospective multicentre observational study conducted in two tertiary centres in Switzerland. A standardized diagnostic evaluation of the underlying cause of hyponatraemia was performed, and an expert panel carefully evaluated volaemic status using clinical criteria. MR-pro ANP levels were compared between patients with hyponatraemia of different aetiologies and for assessment of volume status. Results MR-pro ANP levels were higher in patients with hypervolaemic hyponatraemia compared to patients with hypovolaemic or euvolaemic hyponatraemia ( P = 0.0002). The area under the curve ( AUC) to predict an excess of extracellular fluid volume, compared to euvolaemia, was 0.73 [95% confidence interval ( CI) 0.62-0.84]. Additionally, in multivariate analysis, MR-pro ANP remained an independent predictor of excess extracellular fluid volume after adjustment for congestive heart failure ( P = 0.012). MR-pro ANP predicted the syndrome of inappropriate antidiuresis ( SIAD) versus hypovolaemic and hypervolaemic hyponatraemia with an AUC of 0.77 (95% CI 0.69-0.84). Conclusion MR-pro ANP is associated with extracellular fluid volume in patients with hyponatraemia and remains an independent predictor of hypervolaemia after adjustment for congestive heart failure. MR-pro ANP may be a marker for discrimination between the SIAD and hypovolaemic or hypervolaemic hyponatraemia. [ABSTRACT FROM AUTHOR]