Background: With a general prolongation of survival, brain metastasis (BM) has become a common complication of breast cancer. However, management of BM remains a severe challenge. We hypothesized that bevacizumab (BE) could significantly enhance drug delivery of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in BM of breast cancer, to brain tumors and thereby improve the efficacy. Methods: Breast cancer patients (pts) with BM progression after whole brain radiotherapy (WBRT) were enrolled. Pts received BE 15 mg/kg day 1, and E 70 mg/m²/day, days 2-4, P 70 mg/m²/day, day 2, every 21 days for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. Using a Simon’s optimal two-stage design with 15% as a minimum interest in CNS-OR rate (by intent to treat analysis), 11 pts were needed at the first stage; and a total of 31 evaluable for the whole study. Results: Among 16 pts enrolled from Jan 2011 to Jan 2012, 12 pts were evaluable for treatment response at the time of abstract submission. Median age was 55 (range 34-66); 1 pt was ER+HER2-, 5 pts were HER2+, and 6 pts were ER-HER2-. The median treatment cycles were 4.5 (range 1-6). Nine of 12 pts (75%; 95%CI 42.8-94.5) achieved CNS-OR including 6 pts (50%) with ≥80% and 3 pts (25%) with 50-80% CNS volumetric reduction, respectively. Two pts had non-CNS disease progression while CNS tumors remained under control. The median CNS progression free survival was 6.6 months (95% CI 0.8-12.4). Grade 3 /4 toxicities included neutropenia, leukopenia, anemia, and platelet in 13 (25.5%), 6 (11.8%), 2 (3.9%), and 2 (3.9%) cycles, respectively. Seven pts (58.3%) had received dose reduction to E 60 mg/m² and P 60 mg/m². Early reporting of this study was approved by Data and Safety Monitoring Committeedue to an extremely promising result. Conclusions: BEEP regimen has a significant anti-tumor effect for BM of breast cancer which progresses after WBRT.