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Several clinical trials have shown that in patients with acute myocardial infarction (MI), statin therapy improves cardiovascular (CV) outcomes, but in these trials patients with acute heart failure (HF) were excluded or only a few were included. In patients with chronic HF, statin therapy does not reduce all-cause or CV mortality. We aimed to assess the association between statin therapy and clinical outcomes in the setting of acute HF with systolic dysfunction complicating acute MI.We performed a post-hoc analysis in 6632 patients included in the EPHESUS trial. The mean age of patients was 64 years and 71% were male. Overall, 47% of patients had a statin prescribed at baseline. Cox regression models and a secondary analysis using propensity score matching were fit to assess the association between statin prescription and clinical outcomes. During a mean follow-up of 16 ± 7 months, all-cause death occurred in 385 (12%) patients with and in 647 (18%) patients without a statin (P < 0.001). After extensive adjustment, the risk of all-cause death was 20% lower in patients on statin [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.69–0.92, P = 0.001]. This positive association was mostly due to a lower risk of CV death (HR 0.76, 95% CI 0.65–0.88, P = 0.0002). In contrast, statin use was associated with a higher risk of non-CV hospitalizations (HR 1.16, 95% CI 1.02–1.33, P = 0.02).Our results suggest that patients with acute HF complicating acute MI may benefit from being on statin therapy. Prospective clinical trials are required to validate these findings.