Abstract: Objective To evaluate the efficacy and safety of pemetrexed or raltitrexed in combination with cisplatin as first-line chemotherapy for malignant pleural mesothelioma. Methods A total of 36 patients with malignant pleural mesothelioma who were not candidates for curative surgery admitted to Department of Oncology, First Affiliated Hospital of Liaoning Medical University from January 2010 to January 2013 were randomly divided into RP group (n=18) and PP group (n=18). In RP group, raltitrexed in combination with cisplatin was applied, while in PP group, pemetrexed combined with cisplatin was administered. The efficacy and adverse reactions in two groups were observed and compared. Results No statistically significant differences were found in the objective response rate, disease control rate, median progression-free survival and median overall survival between RP group and PP group (22.2% vs 38.9%, 72.2% vs 83.3%, 5.0 months vs 5.5 months, 11.2 months vs 11.8 months, P＞ 0.05). The incidence of hematological toxicity was higher in PP group than in RP group, but no statistically differences in adverse reaction were found between the two groups (P＞ 0.05). Conclusion The clinical efficacy of the two regimens as first-line chemotherapy for malignant pleural mesothelioma is similar, raltitrexed/cisplatin is a preferred regimen for patients who can not afford pemetrexed or try to avoid hematological toxicity as much as possible.