Background: We report the results of a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients and Methods: 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (AranespR) 300 microg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (VenoferR) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb greater than or equal to 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Results: In intent to treat analyses, the proportion of complete correctors was 24% in group 1, 81% in group 2 (P<0.001 compared with group 1), and 92% in group 3 (P<0.001 compared to group 1, and P=0.099 compared to group 2). Median time to achieve Hb greater than or equal to 13 g/dL was not reached in group 1, 42 days in group 2 (P<0.001 compared to group 1), and 32 days in group 3 (P<0.001 compared to group 1 and P=0.127 compared to group 2). Mean + or - standard deviation total doses of darbepoetin-alfa administered were 1,445 + or - 489 microg in group 2 vs 1,272 + or - 443 microg in group 3 (P=0.06). Eight patients (2 in group 1, 4 in group 2, and 2 in group 3) required red blood cell transfusions on study, including 4 patients following early disease progression. In per protocol analyses, the proportion of complete correctors was 21% in group 1, 80% in group 2 (P<0.001 compared with group 1), and 96% in group 3 (P<0.001 compared to group 1, and P=0.029 compared to group 2). Median time to achieve Hb greater than or equal to 13 g/dL was 190 days in group 1, 44 days in group 2 (P<0.001 compared to group 1), and 31 days in group 3 (P<0.001 compared to group 1 and P=0.025 compared to group 2). There was no difference in ferritin levels, nor in rates of thrombo-embolic events, or other complications among the groups. Conclusions: This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant in intent to treat analyses) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required.