Introduction: Myocardial infarction (MI) is followed by acute changes in serum iron markers. The mechanisms behind this and its long-term impact are unknown. This work aims to explore the role of hepcidin in this context. Methodology: We conducted a clinical study nested within a placebo-controlled randomised trial of IL6 receptor antagonist Tocilizumab in patients with ST-elevation-MI (CT03004703). Changes in heart function, hepcidin, serum iron markers and inflammatory markers were measured. In mice, MI was induced surgically. Heart function was analysed by MRI, serum iron-markers, and myocardial labile iron quantified using iron-caged luciferin. Results: In patients receiving placebo (n=98), hepcidin rises acutely within 24 hours post-MI (p = 0.0003) while serum iron markers drop (p = 0.014). This did not occur in the Tocilizumab group (n=100). Hepcidin levels at 24 hours post-MI correlated with the size of the area at risk (p = 0.032) and predicted elevated NTproBNP (p = 0.007), larger infarct size (p = 0.001), and lower LVEF % (p = 0.029) at 6 months, even after correcting for confounders. In mice, hepcidin levels also rose acutely post-MI, and this was accompanied by increased myocardial LIP in the area at risk. Conclusions: Hepcidin rises acutely post-MI, deriving from the myocardial area at risk, under the influence of IL-6. These changes are accompanied by a drop in serum iron and predict adverse cardiac remodelling. Evidence from the mouse model suggests the impact of hepcidin on adverse cardiac remodelling may relate to excess labile iron retention within the area at risk.