Abstract Background Reduced quality of life during chemotherapy is often due to fatigue and dyspnea caused by chemotherapy-induced anemia. In breast cancer patients the incidence is estimated to be above 50% and rising during the course of treatment resulting as well in therapy delays. Despite red blood cell transfusion the administration of erythrocyte stimulating factors (ESF) serves as a treatment option. In comparison with conventional chemotherapy intense dose dense regimens have proven to be beneficial in high-risk breast cancer patients, but higher incidences of anemia have been reported. In the GAIN trial two dose dense regimens were evaluated and patients received either Darbepoetin alfa or Epoetin beta. The aim of this subanalysis was to analyse the efficacy and safety of the application of two different ESF during adjuvant chemotherapy for primary node positive breast cancer. Methods Patients were randomly assigned to receive three courses each of epirubicin (E), paclitaxel (T), cyclophosphamide (C) all given at 2-week intervals i.v. (idd ETC-regimen) or ddEC followed by paclitaxel weekly (Tw) plus capecitabine (X)(EC-TX-regimen).All patients received either primary prophylaxis with Epoetin beta (Epo) (450IE/kg weekly) or Darbepoetin alfa (D) (4,5μg/kg biweekly).Allocation happened alternately by date of randomization. Patient outcome (rate of anemia and thromboembolic events, disease free survival (DFS), overall survival (OS)), overall and by regimen were compared according to ESF type applied and in subgroups defined by age. Results 2994 patients were randomized to receive one of the dose dense chemotherapies and of these 1482 patients were given Darbepoetin alfa and 1512 received Epoetin beta. In the trial 84.7% of patients suffered from anemia in the Darbepoetin as well as in the Epoetin group and grade 3/4 anemia was observed in 3.6% vs 3.1% of patients, respectively. In the ETC arm anemia rates, especially grade 3/4 were slightly higher, but there was no significant difference within the treatment arms according to ESF applied (anemia any grade: D 86.1% vs. Epo 87.2%; EC-TX: D 83.2% vs. Epo 82.3%). In the ETC arm anemia was most frequently observed in patients aged 60+ years, but there was no significant difference between the ESF (D 90.5% vs. Epo 89.8%). No significant differences in the incidence of anemia by ESF treatment were observed in various age groups of the EC-TX arm. Thromboembolic events occurred in 9.1% in the Darbepoetin group and in 10.1% of patients treated with Epoetin (p=0.355). Interestingly there were more thromboembolic events in the EC-TX arm compared to the ETC arm (p<0.001), but irrespective of the ESF type (EPC: D 7.0% vs. Epo 7.7%; EC-PX: D 11.3% vs. Epo 12.5%). OS and DFS analyses showed no difference between ESF treatment overall as well as stratified by chemotherapy regimen. Conclusion High risk breast cancer patients treated with two different dose dense chemotherapy schedules have comparable incidences of anemia, thromboembolic events and a similar long term outcome if they receive a preventive treatment with either Darbepoetin alfa or Epoetin beta. The trial is financially supported by Amgen and Roche. Citation Format: van Mackelenbergh M, Loibl S, Jackisch C, Lück H-J, Schneeweiss A, Tesch H, Harbeck N, Schmatloch S, Fehm T, Huober J, Müller V, Bauerfeind I, Untch M, von Minckwitz G, Nekljudova V, Möbus V. Efficacy and safety of darbepoetin alfa or epoetin beta in 2994 high risk early breast cancer patients participating in the German adjuvant intergroup node-positive study (GAIN) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-04.