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Aims Acute myocardial infarction complicated by cardiogenic shock (AMICS) is associated with substantial mortality, although there are limited data available on bleeding in this critical condition. This study sought to investigate the incidence and impact of major in-hospital bleeding on all-cause mortality in patients with AMICS who undergo percutaneous coronary intervention (PCI). Methods and results Between 2015 and 2017, a total of 3411 patients hospitalized within 24 h after symptom onset were prospectively enrolled in the Japan Acute Myocardial Infarction Registry (JAMIR) and followed up for a median of 293 (interquartile range, 22–375) days. AMICS developed in 335 (9.8%) patients (mean age, 71.3 ± 13.6 years). Overall, the rate of major in-hospital bleeding (Bleeding Academic Research Consortium types 3 and 5) and in-hospital mortality was 14.6% and 28.7%, respectively. The majority of major in-hospital bleeding (73.5%) occurred within 48 h after PCI. Compared to patients without major in-hospital bleeding, those with it had higher rates of renal failure, left main coronary artery culprit lesion, and intra-aortic balloon pump or extracorporeal membrane oxygenation support, and had longer door-to-device time. The cumulative incidence of 1-year all-cause mortality was significantly higher in the major bleeding group compared to the non-major bleeding group (63.8% vs. 25.5%; log-rank P Conclusions These findings of JAMIR indicate that major in-hospital bleeding is associated with all-cause mortality in patients with AMICS who undergo PCI.