Background: Capecitabine is a well-established treatment option in HER2-negative advanced breast cancer (ABC) patients. Bendamustine is a generally well tolerated cytotoxic drug. Since bendamustine has already shown anticancer activity in ABC we evaluated the efficacy and tolerability of bendamustine in combination with capecitabine in pretreated patients with ABC. Methods: MBC-6 is a non-randomized, multicenter, open-label, single-arm phase II study in patients with HER2-negative ABC (ClinicalTrials.gov: NCT01891227). All patients were pretreated with anthracyclines and/or taxans and had measurable disease according to RECIST 1.1. Patients received 1000 mg/m2 capecitabine twice daily on days 1 to 14 in combination with 80 mg/m2 bendamustine on day 1 and 8 of a 3-week cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), safety and quality of life. Results: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centers. Median age was 60 years (range 29-77). Twenty-five percent of patients had triple-negative disease (TNBC) and 93% showed visceral involvement. Sixty-five percent had received prior chemotherapy in the (neo)adjuvant setting and 63% for ABC (43% one line, 15% two lines, 5% three lines). All patients with ER-positive disease had received prior endocrine therapy. With 20 confirmed PR and 1 confirmed CR, ORR was 53%, 57% in ER-positive and 40% in TNBC. CBR was 60%. At data cut-off on 01/13/16 overall 32 of 40 patients had discontinued treatment with a preliminary median PFS of 8.9 months (95% CI 6.5-12.6). Fourteen patients (35%) experienced at least one drug related non-hematological AE ≥ grade 3 (all grade 3). Three grade 4 neutropenia were observed, but no case of neutropenic fever. One patient died as a result of restrictive cardiomyopathy, where a relationship to capecitabine cannot be excluded, but seems unlikely. Conclusions: The combination of capecitabine and bendamustine shows promising efficacy and a moderate toxicity profile. Further evaluation of this drug combination is warranted. Clinical trial information: NCT01891227