Proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a well-established animal model for the study of relapsing-remitting multiple sclerosis (MS). Here we investigated histomorphological differences between acute and relapse EAE in order to get further insights into the mechanisms that trigger the transition from a relapsing-remitting course to chronic-progressive disease. We found the extent of inflammation to differ in respect to the type of immune cells infiltrating the CNS and the manifestation of edema. Myelin pathology was predominated by demyelinated axons in the acute phase. In relapse EAE the extent of myelin pathology declined and was characterized by a balance between demyelinated and demyelinating nerve fibers. Axonal pathology increased with disease progression and was partly separated from myelin pathology and inflammation. The reported incisive differences between acute and relapse EAE suggest a transition from inflammatory processes to independent neurodegeneration in the disease course.