Selective high-titer anti-tubulin autoantibodies are associated with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Low-titer anti-tubulin autoantibodies are a normal component of some human sera. Analysis of 7 human sera with monoclonal anti-tubulin autoantibodies showed that the epitopes recognized by these antibodies are within central, conserved regions of tubulin. Sera from 3 patients with IgM monoclonal antibodies and CIDP reacted to an epitope spanning aa 301-314 of beta-tubulin, which has some sequence homology to several human viruses. Natural polyclonal anti-tubulin antibodies also bind to central regions of tubulin. In contrast, polyclonal tubulin antibodies induced in mice react to epitopes on the amino- or carboxy-terminal. Selective polyclonal anti-tubulin autoantibodies with low reactivity to other neural antigens are found in about one-half of patients with CIDP.