Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. While both cell-mediated and humoral mechanisms contribute to its pathogenesis, the rapid clinical response to plasmapheresis implicates a circulating factor responsible for peripheral nerve injury. We report that treatment-naïve patients with CIDP show increased serum and CSF levels of the anaphylatoxin C5a and the soluble terminal complement complex (sTCC). Systemic terminal complement activation correlates with clinical disease severity as determined by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. These data indicate that complement activation contributes to peripheral nerve injury and suggest that complement inhibition should be explored for its potential therapeutic merit in CIDP.