Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system, which starts in the majority of patients with a relapsing/remitting MS (RRMS) course , which after several years of disease duration converts into a progressive disease. Since anti-inflammatory therapies and immune modulation exert a beneficial effect at the relapsing/remitting stage of the disease, but not in the progressive stage, the question was raised whether inflammation drives tissue damage in progressive MS at all. We show here that also in progressive MS, inflammation is the driving force for brain injury and that the discrepancy between inflammation-driven tissue injury and response to immunomodulatory therapies can be explained by different pathomechanisms acting in RRMS and progressive MS.