BACKGROUND: Carfilzomib and other proteasome inhibitors (PIs) have revolutionized treatment of multiple myeloma (MM). PIs have proven to be highly effective, but are associated with significant cardiovascular adverse events (AEs). No prior study has compared the cardiotoxicity of carfilzomib against other PI's and all other classes of medications. OBJECTIVES: The purpose of this study is to characterize the cardiotoxicity of carfilzomib with respect to other PIs and all classes of medications using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database and to define the observed cardiotoxicity profile. METHODS: The FAERS database was queried between years 2017 and 2020 to identify AEs associated with PIs. Data extracted included concomitant medications used, type and severity of AEs and patient characteristics including age, sex, and time from medication initiation to adverse event. Cardiotoxicities assessed included acute myocardial infarction, heart failure, and supraventricular tachycardia. The reporting odds ratio (ROR) and information component assessed the strength of association between PIs and cardiotoxicity. RESULTS: Over the study period, 21,026 adverse events were reported in patients taking carfilzomib among 55,195 total adverse events in patients taking PI's were identified from 6,548,048 total events reported in the FAERS database. The most common AE associated with carfilzomib was development of heart failure (1116 adverse events); disproportionality analysis revealed a stronger association with hypertension and QT prolongation with carfilzomib than other PI's. CONCLUSIONS: While they have demonstrated efficacy and revolutionized treatment of MM, carfilzomib and other PI's are associated with cardiotoxicities.