OBJECTIVES: This study sought to determine the efficacy and safety of a novel, pH-neutral formulation of furosemide administered subcutaneously (SC) for treatment of acute decompensated heart failure (HF). BACKGROUND: Congestion requiring intravenous (IV) administration of a diuretic agent is the main reason patients with HF present for acute medical care. METHODS: Outpatients presenting with decompensated HF were randomized to receive a single SC or IV dose of furosemide. Primary outcome was 6-h urine output, and secondary outcomes were weight change, natriuresis, and adverse events. RESULTS: Forty-one patients were randomized: 19 were treated with IV (mean dose: 123 ± 47 mg) and 21 with SC furosemide (fixed dose of 80 mg over 5 h). The 6-h urine output in the IV group was not significantly different from that in the SC furosemide group (median IV: 1,425 ml; interquartile range [IQR]: 1,075 to 1,950 ml; vs. median SC: 1,350 ml; IQR: 900 to 1,900 ml; p = 0.84). Additionally, mean weight loss was not significantly different (-1.5 ± 1.1 kg in the IV group vs. -1.5 ± 1.2 kg in the SC group; p = 0.95). Hourly urine output was significantly higher in the IV group at hour 2 (425 ml in the IV group vs. 250 ml in the SC group; p = 0.02) and higher in the SC group at hour 6 (125 ml, IV group vs. 325 ml, SC group; p = 0.005). Natriuresis was higher in the SC group (IV: 7.3 ± 35.3 mEq/l vs. SC: 32.8 ± 43.6 mEq/l; p = 0.05). There was no worsening renal function, ototoxicity, or skin irritation with either formulation. Thirty-day hospitalization rates were similar. CONCLUSIONS: In this phase II trial, we did not identify significant differences between urine output obtained with pH-neutral furosemide administered SC and that obtained by IV. This method of decongestion may allow treatment at home and reduced HF resources and warrants further investigation. (Sub-Q Versus IV Furosemide in Acute Heart Failure; NCT02579057).