Abstract Aims The use of digitalis has been plagued by controversy since its initial use. We aimed to determine the relationship between digoxin use and outcomes in hospitalized patients with acute coronary syndromes (ACSs) complicated by heart failure (HF) accounting for sex difference and prior heart diseases. Methods and results Of the 25 187 patients presenting with acute HF (Killip class ≥2) in the International Survey of Acute Coronary Syndromes Archives (NCT04008173) registry, 4722 (18.7%) received digoxin on hospital admission. The main outcome measure was all-cause 30-day mortality. Estimates were evaluated by inverse probability of treatment weighting models. Women who received digoxin had a higher rate of death than women who did not receive it [33.8% vs. 29.2%; relative risk (RR) ratio: 1.24; 95% confidence interval (CI): 1.12–1.37]. Similar odds for mortality with digoxin were observed in men (28.5% vs. 24.9%; RR ratio: 1.20; 95% CI: 1.10–1.32). Comparable results were obtained in patients with no prior coronary heart disease (RR ratio: 1.26; 95% CI: 1.10–1.45 in women and RR ratio: 1.21; 95% CI: 1.06–1.39 in men) and those in sinus rhythm at admission (RR ratio: 1.34; 95% CI: 1.15–1.54 in women and RR ratio: 1.26; 95% CI: 1.10–1.45 in men). Conclusion Digoxin therapy is associated with an increased risk of early death among women and men with ACS complicated by HF. This finding highlights the need for re-examination of digoxin use in the clinical setting of ACS.