Aims The pathogenesis of myocardial ischemia-reperfusion injury (MI/R) involves an inflammatory response. Since the four-and-a-half LIM domain-containing protein 2 (Fhl2) has been observed to modulate immune cell migration, we aimed to study the consequences of Fhl2-/- under MI/R with respect to immune reaction, scar formation, and hemodynamic performance. Material and methods In a closed chest model of 1 h MI/R, immune cell invasion of phagocytic monocytes was characterized by flow cytometry and immunohistochemistry. In addition, infarct size was assessed by triphenyltetrazolium chloride/Masson trichrome staining 24 h/21 days after reperfusion and a set of hemodynamic parameters was recorded by catheterisation in Fhl2-/- mice and controls. Key findings While flow cytometry did not reveal differences in myocardial CD45high immune cell infiltrate, histological analysis showed that infiltrating immune cells in Fhl2-/- animals were preferentially located in the perivascular area, whereas in wild type, immune cells were well dispersed within the area at risk. After 24 h and 21 days of reperfusion, infarct size was significantly reduced in Fhl2-/- compared to WT animals. In addition, hemodynamic performance was better in Fhl2-/- mice, compared to WT mice up to day 21 of reperfusion. The loss of Fhl2 leads to an altered immune response to myocardial ischemia, which results in smaller infarcts and better hemodynamic performance up to 21 days after myocardial ischemia reperfusion. Significance Immune cell invasion plays a pivotal role in the context of MI/R. Fhl2 significantly influences immune cell function and immune cell interaction with injured cardiac tissue leading to altered scar composition.