The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.