Single-agent bendamustine has shown promise in the treatment of metastatic breast cancer. As toxicity was low after weekly administration of this drug in other solid tumors, the present double-center phase II trial was conducted to evaluate the efficacy and toxicity of weekly bendamustine as salvage treatment in metastatic breast cancer. A total of 34 patients with anthracycline (88%) and/or taxane (71%) pretreated for metastatic breast cancer received 60 mg/m bendamustine on day 1, 8 and 15 every 28 days for six cycles. In addition, 10 patients with HER2/neu-overexpressing tumors either continued (five patients) or started treatment with 2 mg/kg trastuzumab weekly (loading dose 4 mg/kg) at study entry. Patients had predominantly visceral disease and had received one (88%) or two chemotherapy regimens for metastatic breast cancer. All patients were eligible for toxicity and 27 for response evaluation. No grade 3 or 4 hematologic toxicity occurred. Only three patients experienced grade 3 nonhematologic toxicity. Five patients (19%) reached a partial response. Stable disease for at least 6 months was achieved in eight patients, for a clinical benefit rate of 48%. The median progression-free survival and median overall survival were 6 months (range, 1-16) and 15 months (range, 2-28), respectively. We conclude that weekly bendamustine is a valid treatment option in patients with anthracycline-pretreated and/or taxanepretreated metastatic breast cancer; in particular, due to its low toxicity profile. Future trials should evaluate higher single doses of bendamustine in a weekly schedule.