PURPOSE: To examine the effectiveness and safety of single-isocenter multitarget stereotactic radiosurgery using a volume-adapted dosing strategy in patients with 4 to 10 brain metastases. METHODS AND MATERIALS: Adult patients with 4 to 10 brain metastases were eligible for this prospective trial. The primary endpoint was overall survival. Secondary endpoints were local recurrence, distant brain failure, neurologic death, and rate of adverse events. Exploratory objectives were neurocognition, quality of life, dosimetric data, salvage rate, and radionecrosis. Dose was prescribed in a single fraction per RTOG 90-05 or as 5 Gy × 5 fractions for lesions ≥3 cm diameter, lesions involving critical structures, or single-fraction brain V12Gy >20 mL. RESULTS: Forty patients were treated with median age of 61 years, Karnofsky performance status 90, and 6 brain metastases. Twenty-two patients survived longer than expected from the time of protocol SRS, with 1 living patient who has not reached that milestone. Median overall survival was 8.1 months with a 1-year overall survival of 35.7%. The 1-year local recurrence rate was 5% (10 of 204 of evaluable lesions) in 12.5% (4 of 32) of the patients. Distant brain failure was observed in 19 of 32 patients with a 1-year rate of 35.8%. Grade 1-2 headache was the most common complaint, with no grade 3-5 treatment-related adverse events. Radionecrosis was observed in only 5 lesions, with a 1-year rate of 1.5%. Rate of neurologic death was 20%. Neurocognition and quality of life did not significantly change 3 months after SRS compared with pretreatment. CONCLUSIONS: These results suggest that volume-adapted dosing single-isocenter multitarget stereotactic radiosurgery is an effective and safe treatment for patients with 4 to 10 brain metastases.