The impact of erythropoiesis-stimulating agent (ESA) on cancer patients' survival has recently become a matter of extensive discussion. Studies in solid tumors demonstrated that ESA adversely affects survival. This issue has not been sufficiently studied in patients with multiple myeloma. In this study, which included 323 multiple myeloma patients followed in our Institution between 1988 and 2007, we demonstrated by using a proportional hazards model including multiple covariates (age, LDH, Hb, platelets, serum creatinine, ISS score, β2 microglobulin, and ESA administration) that ESA administration is associated with reduced survival (hazards ratio: 1.88, 95% CI: 1.28–2.77). Anemia, which is considered a predictor for survival, platelets, serum creatinine, ISS score, and LDH, were not significant, whereas, age and β2 microglobulin confirmed their predicting value in the multivariate analysis. With a median follow-up of 31 months (range 1–238), the median survival of patients in the ESA group was 31 months (95% CI: 25–37), whereas in the group without ESA administration it was 67 months (95% CI: 55–79) (P < 0.001). The median progression-free survival for patients in the ESA group was 14 months (95% CI: 12–16), and for the group without ESA it was 30 months (95% CI: 24–36) (P < 0.001). These results indicate that ESA may have a detrimental impact on MM patients' outcomes and, thus, in this context, they should be used with rigorous criteria. © 2008 Wiley-Liss, Inc. Am. J. Hematol., 2008.