Background: Intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) (idd-ETC) resulted in a superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC-T (q3w) chemotherapy in primary breast cancer patients (pts) with ≥4 involved lymph nodes (LN) (Möbus et al, JCO 2010). The GAIN trial had a 2x2 factorial design for investigating two different dose-dense chemotherapy regimens as well as the use of adjuvant ibandronate treatment. Ibandronate results have been reported previously (von Minckwitz et al, JCO 2013). Here we report the final results of the chemotherapy comparison. Methods: Pts were randomized to idd-ETC (E:150 mg/m², T:225 mg/m², C:2500-2000 mg/m², i.v. day 1, q15 for 3 cycles each) or EC followed by T plus capecitabine (X) (EC-TX) (E: 112.5 mg/m² + C: 600 mg/m², i.v. day 1, q 15 for 4 cycles followed by T: 67.5 mg/m² i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m² p.o. day 1-14, q 22 for 4 cycles). After recruitment of 1,500 patients the dose of C was reduced to 2000 mg/m². Pts aged 18-65 years with involved axillary LN were eligible. 3000 pts with 801 events were needed to show an increase of 5-year DFS (primary endpoint) from 75% to 79% for patients receiving EC→TX after 8 years total study duration. Results: 3,023 patients were randomized from 06/2004 until 08/2008. Median age was 50 years; pN1 (37.7%), pN2 (35.4%), pN3 (26.9%); 46.6% were grade 3. With a median follow up of 74 months we observed 644 DFS events (327 with idd-ETC; 317 with EC-TX) (HR 0.94; log-rank p=0.47). 5-year DFS was 80% with idd-ETC and 82% with EC-TX. No different treatment effect was observed in predefined subgroups. 383 pts have died (205 with idd-ETC; 178 with EC-TX) (HR 0.85; log-rank p=0.10). Hematological toxicity was higher in the idd-ETC arm, but 3 and 11 treatment related deaths occurred in the idd-ETC and EC-TX arm, respectively. Conclusions: Both dose-dense regimens achieved a highly favorable 5-year DFS superior to our assumptions mainly based on the preceeding idd-ETC study. The addition of a fourth cytostatic drug (here capecitabine) did not improve efficacy of dose-dense therapy, but led to higher toxicity. Clinical trial information: NCT 001 968 72.