The key role of a blunted production of endogenous erythropoietin (EPO) in determining anemia of patients with multiple myeloma (MM) has been definitively established. Thus, several clinical trials have investigated the effects of recombinant EPO (r-EPO) in anemic MM patients. The results of these studies have demonstrated that r-EPO is a safe and effective drug, which results in an increase in Hb levels in the majority of treated patients. However, several factors, such as serum levels of endogenous EPO, severity of anemia, presence of normal erythroid progenitors, serum levels of some cytokines with inhibitory activity on erythroid function and previous treatments, may significantly affect the possibility of response, thereby suggesting the need for careful selection of MM patients for treatment with r-EPO.