The individual role of tumor necrosis factor receptor 1 (TNFR1) and TNFR2 signaling in experimental autoimmune encephalomeylitis (EAE) was investigated using mice lacking TNFR1 (TNFR1− / −), TNFR2 (TNFR2− / −) as well as double receptor (TNFR1 / 2− / −) and double ligand (TNF / LTα− / −) knockout mice. In wild‐type (wt) mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35 – 55 the clinical course is characterized by an acute disease onset with peak disease scores and a consecutive chronic phase lasting up to 60 days. Compared to control mice, TNF / LTα‐deficient mice showed a significant delay in disease onset and a remarkable reduction in demyelination which was, however, associated with increased inflammation. In TNFR1− / − and TNFR1 / 2− / − mice, the disease course was comparable to TNF / LTα‐deficient mice but rather monophasic and less severe at late time points. Likewise only minimal spinal cord demyelination became apparent. In contrast, the course of EAE in TNFR2− / − mice was severe and associated with remarkable demyelination. Taken together these findings define TNFR1 as crucial mediator in MOG‐induced EAE and suggest a protective role for TNFR2 signaling in the clinical course of EAE.