Erythropoietin (Epo) is the primary hormone that stimulates erythroid proliferation and differentiation through its cell surface receptor (EpoR) on erythroid progenitor cells. Previous studies have suggested that the bone marrow plays an important role in Epo's elimination. The changes in the EpoR mRNA levels and Epo's clearance in the bone marrow of 11 newborn lambs were studied to elucidate the role of EpoR in Epo's clearance under anemic conditions. Epo mRNA levels were measured by realtime polymerase chain reaction, and relative expression of EpoR was calculated by using the comparative CT method. The glyceraldehyde-3-phosphate dehydrogenase housekeeping gene was chosen as a control gene for the calculations. All lambs showed significant increase in bone marrow EpoR mRNA levels after phlebotomy-induced anemia. Epo's clearance determined from simultaneous pharmacokinetic studies with 125I- recombinant human Epo showed a significant increase after phlebotomy-induced anemia that was similar to the increase in EpoR. By day 28 after phlebotomy, EpoR mRNA levels and Epo clearance had returned toward baseline. These results indicate that the changes in Epo's clearance are not caused by body growth but result from significant changes in the pool of EpoR. A linear mixed-effect model was used to evaluate the quantitative relationship between EpoR and Epo's clearance. This analysis demonstrated a highly significant positive linear correlation between EpoR and Epo clearance. Together, these findings provide strong evidence that receptor-mediated Epo clearance is an important route for Epo's elimination. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.