When relapse occurs the treatment of glioblastoma patients remains a challenge for oncologists, the prognosis is poor and no therapy has proven benefit on survival. There are preclinical evidences of a synergism between cisplatin and temozolomide and between cisplatin and thalidomide. In the contest of a phase I and a subsequent phase II study we treated 17 patients with relapsed high-grade malignant glioma with cisplatin plus temozolomide and then with the same combination plus thalidomide. Toxicity was generally manageable but an incidence of 36.4% of vascular thrombo-embolic events was observed in patients treated with thalidomide. Sixteen patients were evaluable for response: 1 patient had a partial response, 8 patients had stable disease and 5 patients had progression. The median time to progression was 4 months (range 0.9–14.9), the progression-free survival at 6 month was 28% and the median overall survival was 7.8+ months (range 2.6–24.2+). Due to the high incidence of thalidomide-associated thrombo-embolic events we continued the phase II study treating patients only with cisplatin and temozolomide. The availability of new antiangiogenetic agents as bevacizumab could in the future improve the efficacy and tolerability of such combinations.