A phase I study was conducted to evaluate the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD)/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at three dose levels (60, 80, and 100 mg/m(2)) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (six with non-small cell lung cancer, four with melanoma, one with breast cancer, and one with neuroendocrine carcinoma). The first two dose levels had three patients each, and the third dose level had six total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m(2). The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. The efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.