Background: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC. Methods: We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250mg/day, gefitinib group) or with concomitant WBRT (40Gy/20f/4w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group. Results: The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib-WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival(OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002). Conclusion: Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.