The purpose of this study is to compare the efficacy and safety of Gefitinib versus VMP in combination with three-dimensional conformal radiotherapy (3D-CRT) for multiple brain metastases from non-small cell lung cancer (NSCLC). A total of 73 NSCLC patients with brain metastases from January 2010 to August 2013 were randomly divided into Gefitinib group (37 patients) and VMP chemotherapy group (36 patients). Patients in VMP group received VM-26 100 mg/day by intravenous injection, from day 1 to day 3, cisplatin 25 mg/m2 by intravenous injection, from day 1 to day 3. One cycle was defined as a 21-day therapy duration, with a total of 3 cycles; 2 cycles were used for consolidation. Patients in Gefitinib group received Gefitinib orally. Both groups received 3D-CRT, DT50 Gy/25f/35d from first day and target areas were treated with whole brain radiotherapy. The results of the study are listed below: There was no significant difference in the short-term effects of the two groups (P > 0.05). Median survival time (MST) of Gefitinib was 13.3 months whereas median survival time of VMP group is 12.7 months (P < 0.05). In Gefitinib group, we did not observe any difference of the median survival time between the patients with and without mutation EGFR. Toxicity of Gefitinib groups were characterized by rash, whereas chemotherapy resulted in hematologic toxicities, which included 6 cases of III/IV leucopenia (17.6 %), 3 cases of anemia (8.8 %), and 5 cases of thrombocytopenia (14.7 %), and non-hematological toxicity which was less serious symptoms for gastrointestinal disorders, hair loss, etc. These adverse reactions can be released after symptomatic treatment. No treatment-related deaths occurred. Two patients in VMP group quit due to IV leucopenia. Both oral Gefitinib and systemic VMP chemotherapy in combination with three-dimensional conformal radiotherapy (3D-CRT) could be used to treat brain metastases from non-small cell lung cancer. There were no difference in the short-term effects of the two groups, but long-term effect of Gefitinib group was slightly better than VMP group. Moreover, Gefitinib group showed low toxicity. All together, our finding implicated that Gefitinib is an effective method for patients with brain metastases from NSCLC.