Abstract Background/Introduction Previous studies have suggested that left ventricular (LV) unloading with an intra-aortic balloon pump (IABP) or percutaneous ventricular assist device (Impella) in combination with extracorporeal membrane oxygenation (ECMO) is associated with lower mortality; however, it is unclear which is better. Purpose This study aimed to evaluate the effectiveness of LV unloading with an Impella versus IABP on in-hospital mortality and other clinical outcomes. Methods Using the Japanese Diagnosis Procedure Combination database from September 28, 2016, to March 31, 2022, we identified inpatients who received an Impella or IABP in combination with ECMO (ECPella or ECMO+IABP group, respectively). The primary outcome was in-hospital mortality and the secondary outcomes were the length of hospital stay, length of ECMO, total hospitalization cost, and complications including major bleeding, an ischemic stroke, vascular complications, and renal replacement therapy during hospitalization. Propensity score matching was performed to compare the outcomes between the groups. We performed sensitivity analyses excluding patients who received extracorporeal cardiopulmonary resuscitation. Results Of 14,525 eligible patients, 603 (4.2%) received ECPella and 13,922 (96%) received ECMO+IABP. After propensity score matching, there was no significant difference in in-hospital mortality between the two groups (58.9% versus 56.6%; risk difference, 2.3%; 95% confidence interval, -3.9% to 8.5%). A Kaplan–Meier analysis with the log-rank test showed no significant difference in the 60-day in-hospital mortality between the two groups (P value = 0.114) (Figure 1). The ECPella group had a longer hospital stay (mean 42.8 days versus 33.7 days; risk difference, 9.1 days; 95% confidence interval, 2.6 to 15.6 days), a higher total hospitalization cost (12,573,000 yen versus 6,857,000 yen; risk differences, 5,716,000 yen; 95% confidence interval, 4,439,000 yen to 6,993,000 yen), and more frequent major bleeding (8.1% versus 5.8%; risk difference, 2.0%; 95% confidence interval, 0.007% to 4.0%), vascular complications (4.1% versus 2.2%; risk difference, 2.0%; 95% confidence interval, 0.04% to 3.9%), and renal replacement therapy during hospitalization (50.6% versus 41.1%; risk difference, 9.5%; 95% confidence interval, 3.0% to 15.9%) than the ECMO+IABP group (Figure 2). The results of the sensitivity analyses, excluding 6,360 patients (44%) who received extracorporeal cardiopulmonary resuscitation, showed similar results to those for the main analyses. Conclusions This nationwide inpatient database study showed that ECPella was not associated with a survival benefit but was associated with a longer hospital stay, a higher total hospitalization cost, and more complications than ECMO+IABP.Figure 1Figure 2