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Background: The prevalence rates of heart failure (HF) and hyperpolypharmacy have increased with the aging population. While a negative impact of hyperpolypharmacy on HF clinical outcomes has already been reported, the effects of hyperpolypharmacy on patients with advanced HF with reduced ejection fraction (HFrEF) undergoing cardiac resynchronization therapy (CRT) remain unclear., Methods: We retrospectively evaluated data from 147 patients with advanced HFrEF who underwent CRT between March 2004 and June 2020. Patients were divided into nonpolypharmacy (<5 medications) and polypharmacy (≥5 medications) groups, as well as nonhyperpolypharmacy (<10 medications) and hyperpolypharmacy (≥10 medications) groups., Results: The mean age of the study population was 70.6 ± 9.7 years, and 90 patients (67.2%) were male. The median number of medications used was 10 (interquartile range: 7-13, range: 2-24); Kaplan-Meier survival analysis revealed that the hyperpolypharmacy group had a significantly worse long-term survival rate in terms of major adverse cardiovascular events (MACE; p  = 0.004) and all-cause mortality ( p  = 0.005). Long-term survival in terms of MACE and all-cause mortality was not significantly different between the polypharmacy with cardiovascular medication and nonpolypharmacy with cardiovascular medication groups. By contrast, the polypharmacy with noncardiovascular medication group had a significantly worse long-term survival rate in terms of MACE ( p  = 0.006) and all-cause mortality ( p  = 0.003) than the nonpolypharmacy with noncardiovascular medication group., Conclusions: Hyperpolypharmacy was significantly associated with adverse cardiovascular outcomes in patients with advanced HFrEF who underwent CRT. Noncardiovascular polypharmacy may underlie the harmful effects of hyperpolypharmacy., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)