Background: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to be an independent risk factor of development of brain metastases (BM). However, the role of HER2 on the radiosensitivity of BM remains controversial. We investigated the efficacy of single fraction stereotactic radiosurgery (SRS) in the treatment of limited BM from breast cancer, based on the HER2 status. Methods: From 2004 to 2010, 57 patients with limited BM were treated with SRS using Leksell Gamma-Knife to a median dose of 20 Gy (range 12-20 Gy) prescribed to the 50% isodose line. The median number of lesions treated were 2 (range 1-7) and the median tumor volume was 92.8 mm³ (range 3.4 -793.7 mm³). There were 27 HER2 positive patients, with 32 ER positive and 22 PR positive patients. Six patients were triple negative. ER/PR information was not available for 4 patients. Overexpression of HER2 was defined as HER2 +++ by immunohistochemistry using the DAKO HercepTest or fluorescent in situ hybridization (FISH) analysis. Time to local recurrence, time to development of new brain metastases, progression-free survival (PFS), and overall survival (OS) were assessed from the date of SRS. Results: With a median follow-up of 11 months (range 1-66 months), 12 patients developed recurrence at the previously treated site (9 HER2 positive patients) and 30 developed new brain metastases (16 HER2 positive patients) The median PFS and OS for all patients were 8 and 16 months respectively. The median PFS for HER2 positive patients compared to HER2 negative patients were 7 and 11 months, respectively (p=0.352). HER2 positive patients had a median OS of 20 months, compared to 14 months in HER2 negative patients (p=0.086). Five patients went on to develop leptomeningeal disease, all of whom were HER2 positive. Conclusions: HER2 overexpression does not increase the risk of recurrence at the site of treatment or appearance of new BM. It does not affect PFS or OS following SRS. However, it remains a risk factor for the development of leptomeningeal disease.