Exogenous recombinant human erythropoietin (rHuEPO) is a beneficial therapeutic agent for correction of anemia in both chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. Transfusion requirements in ESRD patients are reduced significantly and anemia management is much improved. Despite widespread use and near-universal exposure of ESRD patients to the drug, rHuEPO remains an effective and safe product. However, a number of nonhematologic complications are described with rHuEPO therapy. Most notable is hypertension, whereas the connection between seizure and enhanced thrombosis is less clear. A possible complication recently described is exacerbation of proliferative diabetic retinopathy. Finally, other less common adverse effects, although rare in most patients, should be recognized as such by physicians who prescribe rHuEPO.