OBJECTIVES: Tolvaptan is an orally administered selective vasopressin V2-receptor antagonist for hyponatremia treatment. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial showed that tolvaptan, combined with standard therapy, improved many heart failure signs and symptoms without serious adverse events. This study evaluated the hospital resource utilization associated with tolvaptan usage among heart failure (HF) patients with hyponatremia based on the EVEREST trial. METHODS: A cost offset model was constructed to evaluate the impact of tolvaptan on hospital resource utilization among HF patients. The Healthcare Cost and Utilization Project (HCUP) 2008 Nationwide Inpatient Sample (NIS) database was used to estimate hospitalization length of stay (LOS) and hospital cost, for HF-associated diagnosis related group hospitalizations (DRG) of adult patients (age ≥18 years). EVEREST trial data for patients with hyponatremia were used to estimate the reduction of LOS associated with tolvaptan vs. placebo. RESULTS: Among EVEREST trial HF patients with hyponatremia (<135 mEq/L), tolvaptan patients had a shorter hospitalization LOS than placebo patients (9.72 vs. 11.44 days, respectively), with a relative LOS reduction of 15%.  933,189 HF-associated DRG hospitalizations were identified from the HCUP NIS database. The mean LOS was 4.8 days with mean total hospital costs of $7,545, and mean daily hospital costs of $1,562. Using an inpatient tolvaptan treatment duration of 3 days with a daily wholesale acquisition cost of $250, the cost offset model estimated a LOS reduction among US HF hospitalizations of 0.73 days with a hospital cost reduction averaging $1,134 per HF admission.  The cost neutral breakeven mean duration of tolvaptan inpatient therapy is 4.54 days. CONCLUSIONS: Based on the EVEREST trial, tolvaptan is associated with a shorter hospitalization LOS than placebo among hyponatremic HF patients, resulting in an estimated mean hospital cost reduction of $1,134 per admission in the US.