A vascular endothelial growth factor (VEGF) inhibitor might enhance metronomic chemotherapy in previously treated metastatic breast cancer (MBC) patients. Anthracycline and taxane refractory MBC patients were given cyclophosphamide 50 mg p.o. daily, methotrexate 1 mg/kg i.v. every 14 days, and bevacizumab 10 mg/kg i.v. every 14 days. Trastuzumab was added in HER2-overexpressing tumors. 24 patients were enrolled and 22 were evaluable. All tumors had histologic grade II-III and most patients had > or =2 metastatic sites. After a median follow-up of 7.7 months the response rates were: complete response (CR) 0%, partial response (PR) 31.8% (95% CI 13.9- 54.9%), stable disease for >or =24 weeks (SD) 31.8% (95% CI 13.9-54.9%). Clinical benefit (CB= CR + PR + SD>24w) 63.6% (95% CI 40.7-82.8%). Median progression-free survival (PFS) was 7.5 months; overall survival (OS) was 13.6 months. HER2-overexpressing or high proliferative-index tumors had better 6-month PFS (75% vs. 34% in HER-negative tumors, P = 0.043; 67% vs. 0% in Ki-67 > or =20% tumors, P = 0.015). Adverse effects were mild. The combination of bevacizumab and a metronomic-based chemotherapy was effective, well tolerated and provided clinical benefit in heavilytreated MBC patients.