The aim of this study was to systematically review the efficacy and safety of iodine-125 brachytherapy combined with chemotherapy in patients with advanced lung cancer. PubMed, MEDLINE, EBSCO, FMJS and Web of Science were searched to obtain randomized controlled trials (RCTs), published in English and Chinese, until February 2016. The evaluating indicators were complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), one-year overall survival, two-year overall survival and adverse events. Revman 5.2 software was used for data syntheses and analyses. A total of 296 patients enrolled in 5 RCTs were ultimately included in this study based on our selection criteria, and 150 patients received chemotherapy alone, while another 146 patients received the combination therapy of iodine-125 brachytherapy and chemotherapy. The results showed that iodine-125 brachytherapy combined with chemotherapy was superior to chemotherapy alone in CR (risk ratio [RR] = 3.66, 95% confidence interval [CI]: 2.08 to 6.44, p<0.001), PR (RR = 1.47, 95% CI: 1.16 to 1.86, p=0.001), ORR (RR = 1.85, 95% CI: 1.54 to 2.22, p<0.001), DCR (RR = 1.19, 95% CI: 1.10 to 1.29, p<0.001), one-year overall survival (RR = 1.46, 95% CI: 1.12 to 1.92, p=0.006) and PD (RR = 0.20, 95% CI: 0.09 to 0.43, p<0.001); meanwhile, there was no significant difference in two-year overall survival (RR = 1.30, 95% CI: 0.72 to 2.37, p=0.39). In terms of adverse events, the combination therapy significantly increased the incidence of neumothorax (RR = 4.93, 95% CI: 1.94 to 12.55, p=<0.001); however, no significant differences were found in the incidence of other adverse events. This study indicated that the combination therapy of iodine-125 brachytherapy and chemotherapy could improve the therapeutic efficacy of advanced lung cancer without increasing the incidence of adverse events, except pneumothorax.