A 57-year-old patient with Langerhans' cell granulomatosis (LCG) is presented. During 22 years of treatment, there were five relapsing infiltrations at different sites of the skull bones, which were treated by surgery, local radiotherapy, and chemotherapy. During the last relapse, the right temporal bone was infiltrated by granuloma and the petrous bone was destroyed with an intimate spread to the internal carotid artery. After two palliative surgical resections and ineffective radiotherapy, 12 cycles of chemotherapy (vinblastine plus prednisolone) were applied and a clinical remission of the disease was achieved. Special attention is paid to the complexity of diagnosis and choice of therapy. It is concluded that the behavior of LCG may change with time, and assume an aggressive form of the disease. Chemotherapy is the treatment of choice for this type of multifocal malignant form of LCG. Prognosis of the disease is unpredictable.