Anemia is common in patients with chronic heart failure, and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Iron deficient diet was given for 20 weeks in weanling Sprague-Dawley rats to induce IDA, and these rats were studied for the evaluation of molecular mechanisms of cardiac remodeling. Iron deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and vascular endothelial growth factor (VEGF) gene expression increased by 12 weeks of IDA, causing angiogenesis in the heart. Hereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression, maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion with decreased levels of serum Epo concentration and cardiac STAT3 phosphorylation after 20 weeks of IDA compared to 12 weeks. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with beneficial adaptive mechanism of anemia induced cardiac hypertrophy, and latter decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new therapeutic strategy in chronic heart failure with anemia.