Background: Brain metastases (BM) occur in about 10-20% of all cancer patients during the course of their disease. The current standard of care for lesions that cause mass effects is neurosurgical resection followed by adjuvant radiotherapy of the resection cavity. We here report efficacy data of the INTRAMET trial (NCT03226483), which tested intraoperative radiation therapy (IORT) using a high-dose, single fraction to the tumor bed. Methods: Patients ≥18 years and Karnofsky (KPS) ≥50 with suspected BM were included. A frozen-section confirmed metastasis and technically applicable IORT were mandatory. Exclusion criteria were surgical or MRI contraindications, meningeal infiltration, or IORT Dmax doses exceeding 8 Gy at risk structures. IORT was performed after tumor resection in the operating room with a mobile low energy X-ray device emitting a spherical radiation field with a sharp dose gradient. A dose of 30Gy was prescribed to the surface of the resection cavity. The primary endpoint was cumulative local control rate (LCR). Secondary endpoints were incidence of other (distant) BM (RCR), overall survival (OS), time to the next systemic treatment and adverse event rates (AE). Results: In total, 35 of the originally 50 planned patients were recruited. After a pre-specified interim analysis, the study was prematurely halted due to good safety and outcomes profiles. 54.3% were men, the mean age was 64 (45-85) years. The mean follow-up was 25.7 (0.8-64.5) month. At the time of this report, 51.4% of patients were alive. 68.6% primary histologies corresponded to lung primaries. The LCR was 94.3% (95% CI 82.9-98.8%) and RCR was 57.1% (95% CI 40.7-72.4%,). 8.6% patients or lesions developed out of field leptomeningeal progression. The mean OS was 37.4 months (95% CI 28.9-46.9). For those patients undergoing salvage whole brain RT (WBRT), the median initiation time was 147 (20-601) days with a significant survival benefit for those not requiring WBRT (p = 0.027). No significant survival differences were identified according to primary histology (p = 0.618), immunotherapy (p = 0.928), seizures at baseline (p = 0.169), KPS (p = 0.056) or radionecrosis appearance (p = 0.214). Mean time to next systemic treatment was 45.0 (95% CI 35.1-54.8) days. No G4-5 AE related to IORT occurred. The overall radionecrosis (RN) rate was 20% (n = 5 G1, n = 1 G2, n = 1 G3). No risk factors could be associated to RN. Post-surgical seizures were present in 28.6% patients, with eloquent localizations as the only predictive factor (p = 0.008). Conclusions: IORT for resected BM yields excellent local control rates and has a toxicity profile similar to those reported in post-operative SRS trials. By easing a prompt initiation of subsequent systemic treatments, IORT might shorten the overall treatment courses of many cancer patients. Clinical trial information: NCT03226483.