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OBJECTIVE To evaluate the clinical effectiveness of pemetrexed combined with cisplatin for the first-line chemotherapy of patients with advanced non-small-cell lung cancer (NSCLC) and maintenance treatment. PATIENTS AND METHODS 240 advanced NSCLC patients were randomly divided into either a control group (treated with gemcitabine combined with cisplatin) or an observation group (treated with pemetrexed combined with cisplatin). The primary treatment was defined as first-line chemotherapy, and the maintenance treatment was defined as retreatment. The demographic data from both groups were statistically similar. Patients were treated for 21 days for each cycle and underwent between 4 to 6 treatment cycles. RESULTS The mid-and-long term efficacy between groups was compared using efficacy indexes [objective response rate (ORR), disease control rate (DCR), and chemotherapy toxic reaction rate] and progression-free survival (PFS), median survival time, and one-year survival rates. The observation group showed a statically greater (p<0.05) ORR and DCR than the control group. Comparison of the prevalence of toxic reaction above level III between the two groups revealed no statistical difference (p>0.05). The PFS, median survival time, and one-year survival rate of the observation group were statistically longer (p<0.05) than those of the control group. CONCLUSIONS Pemetrexed combined with cisplatin was both safe and efficacious for the first-line chemotherapy of NSCLC patients at a progressive stage and for maintenance treatment.