Description: Aims The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. Methods and results Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T 2 -weighted short tau inversion recovery spin echo imaging, T 2 *-mapping, and T 1 -weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26–40%]. The median in-plane extent of T 2 -weighted ‘hypoenhancement’ in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14–22%; P 〈 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T 2 *-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12–18%; P 〈 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T 2 -weighted hypoenhancement). A substantial drop in absolute T 2 *-values was observed not only in the infarct core and peri-infarct zone, but also in the remote ‘healthy’ myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. Conclusion We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.