BACKGROUND: The four-drug regimen for heart failure with reduced ejection fraction (HFrEF) significantly reduces the risks of hospitalization and mortality. To identify key adverse drug events (ADEs) warranting attention with this regimen, we conducted a real-world pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) events. RESEARCH DESIGN AND METHODS: We collected ADE reports of the four-drug regimen from FAERS that matched this regimen over a ten-year period. Disproportionality analysis and subgroup analysis were performed using four algorithms. Time-to-onset (TTO) analysis was used to assess the temporal risk patterns of ADE occurrence. Lastly, logistic regression was applied to investigate the relationship-value between patient characteristics and ADEs. RESULTS: A total of 1,237 cases with 6,580 ADE reports were collected. Disproportionality analysis identified the most frequent ADEs as hypotension, acute kidney injury (AKI), and hyperkalemia. TTO analysis revealed a median TTO of 39 days for all important medical events, and the median TTO for AKI was 28 days, both fitting an early failure curve. CONCLUSION: In the comprehensive management of HFrEF with the four-drug regimen, in addition to routine monitoring of ADEs such as hypotension and hyperkalemia, early-onset AKI should be a particular focus.