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.