BACKGROUND: Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited. OBJECTIVE: To prospectively investigate the accuracy of the saline infusion test (SIT). METHODS: Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). RESULTS: One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 ± 0.026, 0.878 ± 0.040 and 0.784 ± 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA. CONCLUSION: In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.