This study sought to establish the recommended phase II dose and efficacy of temozolomide (TMZ) with concurrent radiotherapy in patients with brain metastases. Patients were stratified by prior systemic therapy (≤1 vs. ≥2) and enrolled in cohorts of escalating doses of daily TMZ for 14 days (group A: 75, 95, 115, 135, or 150 mg/m(2), group B: 75, 90, 105, 120, or 135 mg/m(2)). Endpoints included safety and clinical activity. For group A (≤1 prior chemotherapy) no dose limiting toxicity was seen at 75 and 95 mg/m(2). Five of eight patients experienced dose limiting toxicities at 115 mg/m(2), thus the recommended phase II dose was 95 mg/m(2). Arm B (≥2 prior chemotherapy regimens) was closed due to poor enrollment. In the phase II portion, 17 patients in group A were treated. There were 0 patients with complete radiographic response, three with a partial response, ten remained stable, and four demonstrated early progression. The 3 and 6 month progression-free survival (PFS) rates were 41 and 18% with a median PFS time of 2.4 months. Overall survival at 3 and 6 months was 53 and 41%, respectively, with a median survival time of 4.1 months. The maximum tolerated dose of daily TMZ with concurrent WBRT was 95 mg/m(2). Despite dose escalation, outcomes did not appear to be improved in the sample treated.