Background: Hyperpolypharmacy is associated with adverse outcomes in older adults, but because literature on its association with cardiovascular (CV) outcomes after acute decompensated heart failure (ADHF) is sparse, we investigated the relationships among hyperpolypharmacy, medication class, and death in patients with HF.Methods and Results: We evaluated the total number of medications prescribed to 884 patients at discharge following ADHF. Patients were categorized into nonpolypharmacy (<5 medications), polypharmacy (5–9 medications), and hyperpolypharmacy (≥10 medications) groups. We examined the relationship of polypharmacy status with the 2-year mortality rate. The proportion of patients taking ≥5 medications was 91.3% (polypharmacy, 55.3%; hyperpolypharmacy, 36.0%). Patients in the hyperpolypharmacy group showed worse outcomes than patients in the other 2 groups (P=0.002). After multivariable adjustment, the total number of medications was significantly associated with an increased risk of death (hazard ratio HR per additional increase in the number of medications, 1.05; 95% confidence interval CI, 1.01–1.10; P=0.027). Although the number of non-CV medications was significantly associated with death (HR, 1.07; 95% CI, 1.02–1.13; P=0.01), the number of CV medications was not (HR, 1.01; 95% CI, 0.92–1.10; P=0.95).Conclusions: Hyperpolypharmacy due to non-CV medications was associated with an elevated risk of death in patients after ADHF, suggesting the importance of a regular review of the prescribed drugs including non-CV medications.