Rosai-Dorfman-Destombes disease is a rare nonmalignant histiocytic condition. Cutaneous disease is common and typically treated with surgical resection, but the optimal medical therapy for inoperable disease has not been determined. We present a 30-year-old man with a large unresectable cutaneous facial mass refractory to corticosteroids and rituximab. He had an excellent response to 13 cycles of lenalidomide 15 mg for 21 out of 28 day cycles and dexamethasone 40 mg/wk with no adverse effects. This is the second case of Rosai-Dorfman-Destombes disease in the literature responsive to lenalidomide-based therapy and confirms the potential efficacy of an immunomodulatory regimen in this disease.