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Objectives: To identify possible etiology-specific differences in preoperative risk factors for major adverse events during Impella 5.5 support in patients with ischemic (ICM) and nonischemic cardiomyopathy (NICM). Methods: From October 2019 to January 2023, 228 Impella 5.5 devices were inserted at our institution. Patients were stratified into ICM (n = 124) and NICM (n = 104) cohorts. The primary outcome was a composite of death/stroke/new-onset dialysis while actively receiving Impella 5.5 support. Random forests identified preoperative factors predictive of the primary outcome separately for each cohort, with ranking by variable importance. Results: The primary outcome occurred in 42 (34%) patients with ICM and 35 (34%) patients with NICM. Twenty-one (17%) patients with ICM and 21 (20%) patients with NICM died on Impella 5.5; stroke occurred in 12 (9.7%) patients with ICM and 3 (2.9%) patients with NICM, and new-onset dialysis was initiated in 23 (19%) patients with ICM and 24 (23%) patients with NICM while actively receiving Impella 5.5 support. Risk factors reflecting systemic and myocardial cellular injury, end-organ and cardiopulmonary failure, right ventricular dysfunction, and smaller left ventricular dimensions were most predictive of adverse outcomes in both cohorts. Indications for Impella 5.5 and device strategy (bridge to recovery, advanced therapies, or decision) were not top risk factors in either cohort. Conclusions: Risk factors related to preoperative stability, right ventricular dysfunction, and left ventricular size were more predictive of adverse outcomes while actively receiving Impella 5.5 support than indication or device strategy. These factors could help identify high-risk patients who may benefit from additional tailored management to reduce their risk for these impactful adverse outcomes while on Impella 5.5 support.