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Background Pemetrexed is a novel folic acid antagonist with multiple targets, which has been widely used in the treatment of non-small cell lung cancer (NSCLC). The objective of this study was to compare the effects and toxicities in NSCLC patients treated with pemetrexed monotherapy versus pemetrexed plus a platinum combination agent, so as to provide a basis for standard second-line chemotherapy. Methods The clinical data of 52 patients with NSCLC who were admitted to Shanghai Chest Hospital from August 2006 to October 2008 were retrospectively analyzed. Ten of the 52 patients received pemetrexed monotherapy, and the other 42 patients received the pemetrexed plus platinum regimen. The primary end point was overall survival (OS). The progression-free survival time (PFS) was analyzed and the effects and toxicities were assessed. Survival analysis was evaluated by Kaplan-Meier method. Single factor analysis and the COX regression model were done to analyze the relationship between the influential factors and the prognosis of disease. The elderly patients (>60 years old) were analyzed separately as a subgroup. Results No statistically significant increase in OS (X~2=0.09, P=0.76), PFS(X~2=0.15, P=0.70), disease control rate (DCR) (X~2=0.06, P=-0.81 ) or 1-year survival rate (X~2=0.33, P=-0.57) was found between the two regimens. Single factor analysis showed that the factors including surgery history, PS score before treatment, clinical stage, and response to second-line treatment influenced the prognosis of NSCLC (all P <0.05). COX regression analysis demonstrated that surgery history (P=0.041) and performance status (PS) score before treatment (P=0.043) may be associated with survival. The toxicity of the two regimens was similar. In the subgroup of elderly patients, no significant difference in OS 0(2=0.01, P=0.94), PFS (X~2=0.14, P=0.70), DCR (X~2=0.004, P=-0.95), or 1-year survival rate (X~2=0.03, P=0.87) was found between the two regimens. The toxicity of combination therapy was significantly higher in terms of hematologic (X~2=9.95, P=-0.01) and gastrointestinal adverse events (X~2=7.66, P=0.03).Conclusiona There is no significant difference in survival or side effects between these two regimens. For elderly patients (≥60), pemetrexed monotherapy shows similar efficacy and a better safety profile when compared with pemetrexed combination therapy.