To compare the outcome of surgical resection followed by whole brain radiotherapy (WBRT) with WBRT alone in patients treated for single brain metastasis. The data from 195 patients with single brain metastases were retrospectively evaluated. Of the 195 patients, 99 underwent resection of the metastasis followed by WBRT and 96 underwent WBRT alone. Seven additional potential prognostic factors were investigated: age, gender, Eastern Cooperative Oncology Group performance score, tumor type, interval between initial tumor diagnosis and WBRT, extracranial metastases, and recursive partitioning analysis class. Both treatment groups were well balanced for these factors. On multivariate analysis, improved survival was associated with resection (relative risk RR, 1.20; 95% confidence interval CI, 1.11-1.31; p < 0.001), lower recursive partitioning analysis class (RR, 1.58; 95% CI, 1.22-2.06; p < 0.001), age < or = 61 years (RR, 1.79; 95% CI, 1.23-2.61; p = 0.002), Eastern Cooperative Oncology Group performance score of 0-1 (RR, 2.47; 95% CI, 1.70-3.59; p < 0.001), and the absence of extracranial metastases (RR, 1.99; 95% CI, 1.41-2.79; p < 0.001). Improved local control was associated with resection (RR, 1.25; 95% CI, 1.11-1.41; p < 0.001) and age < or = 61 years (RR, 1.77; 95% CI, 1.09-2.88; p = 0.020). Improved brain control distant from the original site was associated with lower recursive partitioning analysis class (RR, 1.65; 95% CI, 1.03-2.69; p < 0.035), age < or = 61 years (RR, 1.81; 95% CI, 1.12-2.96; p = 0.016), and the absence of extracranial metastases (RR, 2.42; 95% CI, 1.52-3.88; p < 0.001). Improved control within the entire brain was associated with surgery (RR, 1.24; 95% CI, 1.12-1.38; p < 0.001) and age < or = 61 years (RR, 1.83; 95% CI, 1.21-2.77; p = 0.004). In patients with a single brain metastasis, the addition of resection to WBRT improved survival, local control at the original metastatic site, and control within the entire brain, but did not prevent the development of new brain metastases distant to the original site.