Combination chemotherapy with cisplatin and pemetrexed is the most active first-line regimen for malignant pleural mesothelioma (MPM). However, no drugs have been approved for second-line treatment of MPM, with effective regimens remaining to be identified for patients in relapse. We have now evaluated the combination of cisplatin and pemetrexed for retreatment of patients with recurrent MPM. Four men with MPM, all of whom received initial treatment with cisplatin and pemetrexed, underwent retreatment with this drug combination. Two of the patients achieved an objective response to the first-line chemotherapy with no evidence of disease progression for 6.4 or 11.4 months, respectively. The other two patients had stable disease with a duration of 7.8 or 5.0 months, respectively. The two patients who showed an objective response to first-line chemotherapy showed a partial response to retreatment, with a time to progression of 5.0 or 8.2 months, whereas the other two patients had progressive disease with a time to progression of 1.0 or 1.4 months, respectively. Retreatment with cisplatin plus pemetrexed was generally well tolerated. Retreatment with cisplatin and pemetrexed is a potential therapeutic option for certain patients with recurrent epithelioid MPM, possibly including those who show tumor regression with a time to progression of 6 months or more after the initial chemotherapy. Further studies are warranted to evaluate the efficacy of such retreatment and to clarify the criteria for patient selection.