Long-term prognosis for advanced stages of cutaneous T-cell lymphoma may be beneficially altered with the use of multimodality therapy. However, refractory disease exists in which current therapeutic options fail to halt the progression of disease. We present 3 cases of refractory Sézary syndrome in which the combination of vorinostat and interferon gamma was well tolerated and produced significant clinical improvement. The potential immunologic basis for this is discussed.