Background: Pyruvate Kinase Deficiency (PKD) drastically reduces the lifespan of erythrocytes resulting in, inter alia, jaundice, hypersplenism and dependency on regular blood transfusions due to hemolysis. Splenectomy and blood transfusions do not guarantee an improvement of clinical symptoms and cause severe side effects such as iron overload and risk of infection. Procedure: Treatment with EPO was introduced two months after birth and commenced with a dosage of < 200.0 U/kg subcutaneously twice per week. Results: Hemoglobin concentration (Hb) remained stable at 8.0 g/dl at the age of 12 months and reached a peak of 11.0 g/dl at 20 moths. No further transfusions were necessary since the effect of EPO set in. Mean corpuscular volume (MCV) showed a slower increase than the number of reticulocytes proving that treatment with EPO improved the maturation of reticulocytes to adult erythrocytes thereby overcoming ineffective erythropoiesis. Iron overload due to prior transfusions was reduced, hypersplenism and compromised liver function were not present at any time. The child’s health and neurological development were in line with its age always. Conclusions: Treatment with EPO overcomes ineffective erythropoiesis in patients with a measurable residual activity of PK preventing the risks and side effects of current standard treatment strategies