Multicentric reticulohistyocytosis (MRH) is a rare multisystemic non-Langerhans histiocytosis characterized by cutaneous nodules and severe destructive polyarthritis, sometimes associated with constitutional symptoms and various organ involvements. Its treatment remains empirical and challenging. We first report herein, the successful treatment of a multicentric reticulohistiocytosis patient with anakinra based on cutaneous biopsy immunostaining and serum cytokines features. A first-line treatment associating methotrexate, cortisone and hydoxychloroquine showed none improvement. Therefore, while further tests were performed to rule out an associated malignancy, auto-immune disease or mycobacterial infection, a treatment with anakinra was chosen instead of anti-TNF-alpha drugs. As soon as the 5th day, anakinra allowed control of fever, then rapid improvement of constitutional symptoms, arthritis, cutaneous lesions, and normalization of C-reactive protein, IL-6, and especially IL-1β levels. Then methotrexate was added, while anakinra was removed at the 12th month, with persistent and complete remission over the two-year follow up. Further assessment of IL-1 pathogenic role and blockade on larger cohorts of patient could open new therapeutic perspectives for refractory/relapsing MRH, considering the good tolerance profile of specific targeting drugs.