The transition from day to night is associated with a pronounced decline in diuresis with reductions in the amount of excreted water, electrolytes and other end-products of our metabolism. Failure to do so leads to a large urine output at night, a condition known as nocturnal polyuria, encountered in a large proportion of children with nocturnal enuresis. The aim of this study was to clarify the mechanisms responsible for the nocturnal polyuria seen in enuretics with inadequate response to dDAVP. Forty six enuretics (7-14 years of age) and 15 age-matched controls were admitted for a 24-h protocol with standardized fluid and sodium intake, comprising urine collections, blood sampling and blood pressure monitoring. We included patients with severe enuresis (5 ± 1 wet-nights per week) showing less than 50% reduction in wet nights on dDAVP. We characterized the patients according on the basis of their nocturnal urine production. The children with nocturnal polyuria excreted larger amounts of sodium and urea at night than non-polyurics and controls. Solute free water reabsorption as well as the urinary AVP and aquaporin 2 excretion was normal in polyurics and no differences were found in ANP, angiotensin II, aldosterone and renin levels. Urinary prostaglandin E2 excretion was significantly higher in polyurics. The nocturnal polyuria in children with dDAVP resistant nocturnal enuresis seems to be the result of augmented sodium and urea excretion. The high urinary PGE₂ levels found in these children point towards a role for increased prostaglandin synthesis in the pathogenesis of enuresis related polyuria.