Advances in chemotherapy for breast cancer (BC) have prolonged overall survival, especially for patients with human epidermal growth factor receptor-2 (HER2) positive cancer. We evaluated the effectiveness and limitations of stereotactic radiosurgery (SRS) for brain metastases (BM) from BC in conjunction with molecular targeting chemotherapy. Outcomes were retrospectively reviewed in 80 consecutive patients who underwent gamma knife SRS for BM from BC between January 2009 and February 2012. The overall survival (OS), neurological death-free survival (NS) and local tumor control endpoints were calculated, and prognostic factors were investigated using proportional hazards models. In 40 patients with HER2-overexpression, treatment results were compared between two sub-groups: lapatinib-based therapy (24 patients) versus non-lapatinib-based therapy (16 patients). The rates of 1- and 2-year OS after SRS were 50 and 26 %, respectively. The median survival time (MST) was 11.4 months. HER2-overexpression (P < 0.001), recursive partitioning analysis class (P = 0.018) and total planning target volume on initial SRS (P = 0.004) were associated with OS. The MSTs in HER2-positive and -negative patients were 16.6 and 7.1 months, respectively (P = 0.001). The rates of 1- and 2-year NS were 90 and 78 %, respectively. The rates of 1- and 2-year local tumor control were 84 and 70 %, respectively. Factors associated with local tumor control included lesion volume (P < 0.001) and peripheral dose (P = 0.003). In sub-analysis of patients with HER2-overexpression, lapatinib-based chemotherapy was also associated with better local tumor control (P = 0.002). The 1-year local tumor control rate of the lapatinib group was significantly better than that of the non-lapatinib group (86 vs. 69 %, P < 0.001). SRS is a safe and effective management option for selected patients with BM from BC. Patients with HER2-overexpressing tumors were found to be a distinct subgroup for which a longer survival time can be expected. Synergistic anti-tumor effects of lapatinib on BM in conjunction with SRS were suggested.