BACKGROUND: The interstitial fluid compartment is disproportionally expanded in heart failure (HF). Enhancing sweat rate removes fluids and sodium directly from the interstitial compartment. OBJECTIVES: To study the feasibility and efficacy of direct interstitial decongestion in hospitalized HF patients. METHODS: We used a device designed to enhance fluid and salt expulsion via the eccrine sweat glands. Patients were treated for 1 to 6 days in the hospital. Following discharge, home therapy continued for 30 to 60 days (1-4 treatments/week). The primary efficacy endpoint for the in-hospital phase was a fluid loss of ≥500 mL per ≥4 hours per treatment. Secondary performance endpoints included changes in congestion score and N-terminal pro b-type natriuretic peptide (NT-proBNP) levels, evaluated for each phase separately. RESULTS: We studied 15 patients, 12 completing both the hospital and home phases. During the in-hospital phase, median weight change due to device therapy was 2.4 kg (interquartile range [IQR] 2.20-3.77), and the primary endpoint was met in 86% of treatment sessions. During the home treatment, median weight loss was 3.1 kg (IQR 0.6 to 7.4 Kg). Congestion score declined from 6 (IQR 6-7) to 1 (IQR 1-1.5) at the end of home therapy (P = 0.002). Median NT-proBNP levels decreased from 7732 (IQR 4694-9746) to 4984 pg/mL (IQR 3559-8950, P = 0.01) during the hospital phase and to 3596 ng/mL (IQR 1640-5742, P = 0.02) at the end of home therapy. CONCLUSION: Fluid removal via the skin is an effective strategy for enhancing decongestion in hospitalized patients with acute decompensated heart failure. Following hospital discharge, device therapy was associated with additional improvement in decongestion.