Background: The results of an international, multicenter, randomized, double-blind, controlled study assessing the efficacy and safety of lenalidomide treatment in patients with refractory stage IV metastatic malignant melanoma are reported. Methods: The study compared treatment with lenalidomide (25 mg/d on Days 1-21 of a 28-day cycle) to placebo in 306 patients with metastatic malignant melanoma. Treatment was continued until progression of disease or unacceptable toxicity. Results: There were no significant differences between lenalidomide and placebo in overall survival (median 5.9 months vs 7.4 months, respectively; P = .32), time to progression (median 3.0 months vs 2.1 months; P = .19), or Response Evaluation Criteria in Solid Tumors tumor response (5.3% vs 5.8%; P = .82). None of the patients given placebo discontinued treatment because of treatment-related adverse events, compared with 4.6% of those treated with lenalidomide. Treatment-related myelosuppression was observed in 2.0% of patients treated with placebo and 7.3% of patients treated with lenalidomide. Conclusions: This study showed that treatment with lenalidomide (25 mg/d) has a manageable safety profile in patients with previously treated metastatic malignant melanoma but no benefit in tumor response, time to progression, or overall survival in these patients. Future trials for treatment of metastatic malignant melanoma with lenalidomide should focus on its use in combination therapies.