PURPOSE: To retrospectively report the outcomes of a large multicenter cohort of patients treated with surgery and hypofractionated stereotactic radiation therapy (HFSRT) to the resection cavities of brain metastases (BMs). METHODS AND MATERIALS: Between March 2008 and February 2015, 181 patients with no prior whole-brain radiation therapy (WBRT) were treated by HFSRT to the surgical bed of BM at the dose of 33 Gy (3 × 11 Gy). The primary endpoint was local control. Secondary endpoints were distant brain control, overall survival (OS), risk of radionecrosis, and leptomeningeal disease (LMD). RESULTS: Of the 189 resected lesions, 44% were metastatic from a non-small cell lung cancer primary tumor, and 76% of patients had a single BM at the time of treatment. With a median follow-up of 15 months, the 6- and 12-month local control rates were 93% and 88%, respectively. On multivariate analysis, planning target volume (P=.005), graded prognostic assessment score (P=.021), and meningeal contact of BM (P=.032) were predictive of local failure. The 6- and 12-month distant brain control rates were 70% and 61%, respectively. Twenty-six patients (14%) developed signs of LMD at a median time of 3.8 months. The preoperative tumor volume was predictive of LMD (P=.029). The median OS was 17 months. The 6-, 12-, and 24-month OS rates were 79%, 62%, and 39%, respectively. Recursive partitioning analysis class 3 (P=.02), piecemeal resection (P=.017), and an increasing number of BMs (P<.01) were independent unfavorable prognostic factors for OS. Fifty-four patients (30%) were subsequently treated with salvage WBRT at a median time of 6.5 months, and 41% were reirradiated with SRT. Radionecrosis occurred in 19% of cases at a median time of 15 months and was associated with the infratentorial location of the BM (P=.0025). CONCLUSIONS: This study demonstrated the safety and efficacy of a 3 × 11 Gy HFSRT regimen for the irradiation of BMs resection cavities. It was an alternative to adjuvant WBRT.