Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.