Background: Local control of brain metastases reduces risk of death from intracranial progression and improves survival in selected patients. Volumetric modulated arc therapy can deliver a fraction of whole brain radiotherapy (WBRT) and a simultaneous integrated boost (SIB) to multiple brain metastases in about 5 minutes. This is the first registered clinical trial (NCT01046123) to report WBRT and SIB for up to 10 brain metastases. Methods: Sixty subjects with 1-10 brain metastases were accrued to a single-institution phase II study of a 5-fraction course of 20 Gy WBRT and 50 Gy SIB. Eligible subjects had Karnofsky Performance Status (KPS) 70 - 100, maximum diameter of the largest metastasis ≤ 3 cm, and estimated ≥ 6-month median life expectancy. The phase II primary endpoint was a comparison of 3-month local control with that of the WBRT (37.5 Gy/15) and stereotactic radiosurgery (SRS: 15-24 Gy/1) arm of the RTOG 95-08 study (90%). Overall survival for subgroups with 1-3 and 4-10 metastases were compared. Results: The median number of brain metastases was 3 (range: 1-10). Known prognostic factors for overall survival in the 1-3 subgroup (n = 33) and the 4-10 subgroup (n = 27) were not significantly different. The cancers were: 53% lung, 32% breast and 15% other. The minimum follow-up was 5 months and the median follow-up was 9 months. The 3-month radiographic responses were: 10% complete, 48% partial, 33% stable (90% local control) and 10% progressive disease. Grade 3-4 radionecrosis occurred in 7% (4/60) of subjects at a median of 9 months. The median survival was 10 months in the 1-3 subgroup and 12 months in the 4-10 subgroup (p = 0.8). Multivariable analysis of overall survival showed that KPS 70-80 (HR = 3.2, p < 0.004), extracranial disease (HR = 2.9, p = 0.04) and no use of targeted systemic therapy (HR = 7.5, p = 0.0003) were associated with worse survival, but age (HR = 0.98, p = 0.1) and number of metastases 1-3 vs. 4-10 (HR = 1.1, P = 0.8) were not. Conclusions: WBRT and SIB had similar 3-month local control to the WBRT and SRS arm of RTOG 95-08. Equivalent survival of the 1-3 and 4-10 subgroups justifies including selected patients with 4-10 brain metastases in phase III trials for brain metastases. Clinical trial information: NCT01046123.