Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment.