Autoantibodies to myeloperoxidase (MPO) are a subset of anti‐neutrophil cytoplasmic antibody (ANCA, MPO‐ANCA) detected in the sera of some patients with primary systemic vasculitis. The titer of MPO‐ANCA does not always reflect disease activity and this inconsistency may be attributable to differences in epitopic specificity by MPO‐ANCA among various patients with vasculitis. Epitope analysis may also explain the occurrence of MPO‐ANCA in different vasculitic syndromes. We screened the sera of 148 MPO‐ANCA positive patients from six vasculitic syndromes: rapidly progressive gromerulonephritis (RPGN), microscopic polyangiitis (MPA), idiopathic crescentic glomerulonephritis (I‐CrGN), classic polyangiitis nodosa (cPAN), Churg‐Strauss syndrome (CSS), Kawasaki disease (KD); and from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The sera were collected by the Intractable Vasculitis Research Project Group in Japan. No serum showed epitopes La and Lb of light chain of MPO, and sera with 68.6% of patients showed a positive reaction to one or more epitopes in heavy chain of MPO. Analysis of binding level showed that RPGN, I‐CrGN and MPA sera mainly reacted to the Ha epitope at the N‐termimus of the MPO heavy chain, CSS sera reacted to Ha and the Hf epitope close to the C‐terminus of the MPO heavy chain, KD reacted mainly to Hf, while SLE and RA sera reacted to all epitopes. These results suggest that MPO‐ANCA recognizing specific regions of the N‐terminus of the MPO H‐chain confer an increased risk of vasculitis RPGN, I‐CrGN, MPA and CSS. Furthermore, the epitopic specificity of MPO‐ANCA differentiates vasculitic from non‐vasculitic syndromes associated with MPO‐ANCA positivity and differentiates in the cirtain type of vasculitis from various vasculitic syndromes. In particular, vasculitic syndromes associated with kidney involvement had similar epitopic reactivity which suggests that this pattern confers an increased risk of vasculitis.