Objective: To review and compare the data concerning the clinical activity of epoetin alfa versus darbepoetin alfa when administered to patients with cancer who are experiencing treatment-related anemia. Data Sources: English-language publications from the MEDLINE database (1990–June 2005), published articles, and meeting abstracts were reviewed. Study Selection and Data Extraction: Relevant data were extracted from published reports and abstracts on studies of humans with cancer who developed treatment-related anemia and were treated with epoetin alfa or darbepoetin alfa. Data Synthesis: Epoetin alfa and darbepoetin alfa are similar agents with identical indications for treatment of anemia in patients with cancer. Clinical trials have demonstrated that both agents can significantly improve hemoglobin levels, reduce transfusion requirements, and improve quality of life. Epoetin alfa is approved for administration at a dose of 150 units/kg subcutaneously 3 times per week, and darbepoetin alfa is approved for administration at a dose of 2.25 units/kg once a week. Clinical studies have demonstrated that epoetin alfa may be administered at 40 000 units once a week and that darbepoetin alfa may be administered at 200 μg every 2 weeks without loss of efficacy. Cost analysis, based on the average wholesale price of each drug alone administered for 12 weeks at Food and Drug Administration–approved doses, revealed that epoetin alfa is less expensive than darbepoetin alfa. When they are administered in the extended schedules, the cost of darbepoetin alfa is slightly less than that of epoetin alfa. However, the total expense associated with the extended schedule of either agent is further reduced by a reduction in other costs associated with drug administration. Conclusions: Epoetin alfa and darbepoetin alfa have identical indications for treatment of anemia in patients receiving cancer chemotherapy. Clinical trials have demonstrated similar activities with both agents. Darbepoetin alfa, with a longer half-life, can be administered less frequently, saving costs as well as reducing patient office visits.