Purpose:To examine the outcomes of patients with a single brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). Methods and Materials:We reviewed the medical records of 27 patients treated at our institution between 2000 and 2007 with a single radioresistant brain metastasis. Patients were treated with Gamma Knife based SRS. Tumor histologies included renal cell carcinoma and melanoma. Results:Patients were treated to a median marginal dose was 20 Gy (range, 15–22 Gy). At follow-up intervals ranging from 1.8 to 23.2 months, the radiographic responses were as follows: progression in 7 patients; stable in 5 patients; and shrinkage in 15 patients. Fifteen patients (56%) developed distant brain failure. Seven of the 27 patients were alive at last follow-up. The 3-, 6-, 9-, 12-, and 18-months after SRS local control rates were 82.8%, 77.9%, 69.3%, 69.3%, and 55.4%, respectively. None of the 5 patients who received WBRT developed distant brain failure although the follow-up intervals were short (range, 3.5–13.7 months; median, 5.1 months). WBRT did not appear to affect local control, progression free survival, and overall survival (P = 0.32, 0.87, 0.69). One patient developed worsening of symptoms attributable to SRS. Conclusions:Gamma Knife SRS is a safe and feasible strategy for treatment of patients with a single radioresistant brain metastasis. Radiosurgery alone is a reasonable treatment option, but may carry a greater likelihood of distant brain recurrence.