Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs). This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 2.8%, adj.ROR = 2.78 95% CI: 2.21-3.51), cardiomyopathy (n = 69 2.6%, adj.ROR = 3.51 2.42-5.09), pleural disorders (n = 46 1.7%, adj.ROR = 3.91 2.92-5.23), and pericardial diseases (n = 11 0.4%, adj.ROR = 2.26 1.25-4.09, all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 1.6%, adj.ROR = 1.80 1.24-2.62, IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 1.04-3.18 and adj.ROR = 2.86 1.18-6.93, respectively). Finally, the fatality rate of CPAEs was 30.9%. In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients. Display omitted