Objective To analyze the efficacy and safety of CyberKnife combined with temozolomide (TMZ) in treatment of brain metastasis of non-small cell lung cancer (NSCLC). Methods From March 2013 to March 2016, 62 NSCLC patients with brain metastases in department of oncology of the 187th Hospital of PLA were divided into two groups according to the random number table method, the CyberKnife combined with TMZ group (CyberKnife + TMZ group, 31 cases) and simple CyberKnife group (CyberKnife group, 31 cases). Hypofractionated radiation of CyberKnife was given 18-36 Gy in 1-5 fractions of 5-25 Gy. CyberKnife+ TMZ group was given temozolomide 150 mg·m-2·d-1 for 5 days in first cycle, then every 28 days they received temozolomide therapy from the second to the sixth cycles: 200 mg·m-2·d-1 for 5 days. The clinical symptom remission rate after the treatment of CyberKnife in one week, the effective rate after CyberKnife in 3 months, the median intracranial progression-free survival time, overall survival, and the incidences of adverse reaction were comparatively analyzed. Results The clinical symptom remission rates of CyberKnife+TMZ group and CyberKnife group after the treatment of CyberKnife in one week were 93.6 ％ (29/31) and 96.8 ％ (30/31). There was no significant difference in the clinical symptom remission rates (χ2= 1.207, P=0.547). The effective rates of the two groups after CyberKnife in 3 months were 93.6 ％ (29/31) and 90.3 ％(28/31). There was no significant difference in the effective rates (χ2 = 0.695, P= 0.706). The median intracranial progression-free survival time in CyberKnife + TMZ group (14.0 months) was significantly higher than that in the CyberKnife group (9 months) (χ2=8.977, P=0.003), and the median overall survival time in CyberKnife + TMZ group (15.0 months) was also significantly higher than that in the CyberKnife group (12.0 months) (χ2 = 5.190, P= 0.023). There was no significant difference in the adverse reaction of the central nervous system between the two groups (χ2=0.746, P=0.689), but the adverse reactions of the digestive system (χ2 = 6.062, P= 0.014) and the hematologic system (χ2 = 6.613, P= 0.010) in CyberKnife + TMZ group were significantly higher than those in the CyberKnife group. Systemic adverse reactions of the two groups were tolerated by most patients. Conclusions CyberKnife combined with TMZ is a feasible therapeutic option for NSCLC patients with brain metastases. This therapy can improve the median survival time to cerebral progression of the disease and the median overall survival time.