The pathogenesis of inflammatory autoimmune diseases of the peripheral nervous system, leading to demyelination and/or axonal damage, remains incompletely understood. In particular, it is controversial regarding the extent to which (i) autoimmune-mediated destruction of peripheral nerves results in secondary damage of the central nervous system, and (ii) CD4 and CD8 T cells contribute to disease. To address these issues, we applied the murine model of P0(106-125)-induced experimental autoimmune neuritis. Immunization of C57BL/6 mice with P0(106-125) resulted in severe axonal damage and mild demyelination. Importantly, these mice developed a "dying-back" axonopathy with apoptosis of a large fraction of neurons in the anterior horn of the lumbar and thoracic spinal cord and a progressive neurogenic muscular atrophy. T cell-depletion experiments identified CD4, but not CD8, T cells as important mediators of experimental autoimmune neuritis. CD4 T cells represented the major cellular source of antigen-specific interferon-gamma and interleukin-17 production, regulated the number of tumor necrosis factor-positive and inducible nitric oxide synthase-positive macrophages in the diseased sciatic nerve, and mediated axonal damage and subsequent neuronal apoptosis and neurogenic muscular atrophy. In contrast, the demyelination of peripheral nerves was only slightly ameliorated in CD4 T cell-depleted mice. In conclusion, P0(106-125)-induced experimental autoimmune neuritis is a CD4 T cell-mediated autoimmune disease that affects both the peripheral and central nervous systems.