A phase 2 multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of 6 prior treatment regimens, including a median of 4 systemic therapies. Patients achieved an overall response rate of 28% (9 patients), and all were partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25-mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain, and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25(+) T cells and CD4(+) T-cell numbers. Skin lesions showed a trend for increased CD8, CD25, and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory cutaneous T-cell lymphomas, along with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT00466921.