After failure of erythropoiesis-stimulating agents (ESA), Lenalidomide (LEN) yields red blood cells (RBC) transfusion independence (TI) in 20-30% of lower risk non-del5q MDS. Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement 6 RBC units/8weeks) lower risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg/day, 21 days/4 weeks (L arm) or LEN (same schedule)+erythropoietin (EPO) beta, 60 000 U/week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles (primary endpoint) was 23.1% (95% CI: 13.5-35.2) in the L arm and 39.4% (95%CI: 27.6-52.2) in the LE arm (P=0.044), while RBC transfusion independence (TI) was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the 2 arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower risk non-del5q MDS patients with anemia resistant to ESA.Leukemia accepted article preview online, 26 October 2015. doi:10.1038/leu.2015.296.