Aims Polypharmacy, defined as the concurrent use of >= 5 medications, is prevalent among older adults with heart failure (HF). While guideline-directed HF medications provide therapeutic benefits, non-HF polypharmacy, particularly involving inappropriate medications, may lead to adverse outcomes. The international REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure (REPORT-HF), the largest available global acute HF registry, was used to examine the prevalence, clinical correlates, and 1-year outcome associations of non-HF polypharmacy. Methods and results Medication counts were classified as no polypharmacy (<5), polypharmacy (5-9), and hyper-polypharmacy (>= 10). Potentially harmful medications were identified using the 2016 American Heart Association scientific statement. Multivariable regression models examined correlates of polypharmacy and 1-year mortality. Among 18 030 patients (66 +/- 14 years, 39% women), 39% had polypharmacy and 9% had hyper-polypharmacy (63% and 25%, respectively, if including HF medications). Non-HF polypharmacy was more common in older white patients from high-income countries, with preserved ejection fraction and high comorbidity burden. Patients with greater non-HF medication use were less likely to receive guideline-directed HF medications and more likely to take medications that can worsen HF. Crude hazard ratios (HRs) for 1-year mortality were 1.16 (95% confidence interval [CI] 1.08-1.25) for polypharmacy and 1.46 (95% CI 1.31-1.63) for hyper-polypharmacy versus no polypharmacy. After adjustment, hyper-polypharmacy remained associated with increased mortality (HR 1.16, 95% CI 1.01-1.33). Conclusions Non-HF polypharmacy in HF is common worldwide, particularly in high-income regions. Its association with reduced use of guideline-directed HF medications and higher usage of medications causing or worsening HF, as well as elevated 1-year mortality, underscores the importance of addressing polypharmacy in HF. [GRAPHICS]