Ischemia of the myocardium is generally accepted to be characterized by swelling of myocytes resulting in cardiac dysfunction. However, data are limited concerning the molecular mechanisms of fast water fluxes across cell membranes in ischemic hearts. Since aquaporin-4 (AQP4) is a water channel with an enormous water flux capacity, we investigated in this study whether this water channel protein might play a role in myocyte swelling following myocardial infarction. For this purpose, we studied the expression of AQP4 mRNA at different time points of ischemia in a murine model of myocardial infarction. We observed a significant correlation between the upregulation of AQP4 mRNA and the size of the infarction. In situ hybridization experiments showed comparably higher expression levels of AQP4 mRNA in ischemic myocytes, and anti-AQP4 immunoreactivity was found to be stronger in the sarcolemma of ischemic myocytes. Our findings imply a role of AQP4 in the formation of myocardial edema and this might be important for future prevention and treatment strategies of this distressing situation in order to minimize cardiac dysfunction and mortality in a variety of cardiac diseases in which cell swelling is prevalent.