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Background: Treatment options to address the hyponatremia induced by the syndrome of inappropriate antidiuresis (SIAD) are inadequate. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and therefore, might offer a novel treatment option for SIAD., Methods: In this double-blind, randomized trial, we recruited 88 hospitalized patients with SIAD-induced hyponatremia <130 mmol/L at the University Hospital Basel from September 2016 until January 2019 and assigned patients to receive, in addition to standard fluid restriction of <1000 ml/24 h, a once-daily dose of oral empagliflozin or placebo for 4 days. The primary end point was the absolute change in plasma sodium concentration after 4 days of treatment. Secondary end points included predisposing factors for treatment response and safety of the intervention., Results: Of the 87 patients who completed the trial, 43 (49%) received treatment with empagliflozin, and 44 (51%) received placebo. Baseline plasma sodium concentrations were similar for the two groups (median 125.5 mmol/L for the empaflozin group and median 126 mmol/L for the placebo group). Patients treated with empagliflozin had a significantly higher increase of median plasma sodium concentration compared with those receiving placebo (10 versus 7 mmol/L, respectively; P =0.04). Profound hyponatremia (<125 mmol/L) and lower baseline osmolality levels increased the likelihood of response to treatment with empagliflozin. Treatment was well tolerated, and no events of hypoglycemia or hypotension occurred among those receiving empagliflozin., Conclusions: Among hospitalized patients with SIAD treated with fluid restriction, those who received empagliflozin had a larger increase in plasma sodium levels compared with those who received placebo. This finding indicates that empagliflozin warrants further study as a treatment for the disorder., (Copyright © 2020 by the American Society of Nephrology.)