The effect of anemia on the coronary microcirculation was studied in young male rats. Chronic anemia resulted in increased left ventricular end-diastolic pressure and decreased functional reserve. Cardiac mass in anemic animals increased by 25%. Capillary and arteriolar densities in these hearts remained unchanged, indicating angiogenesis in this experimental situation (estimated aggregate capillary length in the left ventricle of anemic hearts was 3.06 km compared with 2.35 km in control hearts). Capillary hematocrit was decreased in chronic anemia less than systemic hematocrit: from 25 to 18% in anemia versus 45 to 28% in controls. Capillary hematocrit and red blood cell spacing were also studied after acute blood withdrawal. Here, capillary hematocrit was preserved even more: 22 versus 24% in systemic hematocrit. Finally, the same was studied in isolated hearts perfused with solutions of various hematocrits. After perfusion with low-hematocrit solution (14%), the capillary hematocrit (24%) was even higher than the perfusate hematocrit! In conclusion, we found evidence of angiogenesis in cardiomegaly induced by chronic anemia. Microvascular growth was accompanied by advantageous regulation of red blood cell spacing within these vessels. This was even more pronounced during acute hemodilution and in isolated perfused hearts.