Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis and renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the role of autoreactive MPO-specific CD4⁺ T cells is uncertain. By screening overlapping peptides of 20 amino acids spanning the MPO molecule, we identified an immunodominant MPO CD4⁺ T-cell epitope (MPO_409–428). Immunizing C57BL/6 mice with MPO_409–428 induced focal necrotizing glomerulonephritis similar to that seen after whole MPO immunization, when MPO was deposited in glomeruli. Transfer of an MPO_409–428-specific CD4⁺ T-cell clone to Rag1^−/− mice induced focal necrotizing glomerulonephritis when glomerular MPO deposition was induced either by passive transfer of MPO-ANCA and LPS or by planting MPO_409–428 conjugated to a murine antiglomerular basement membrane mAb. MPO_409–428 also induced biologically active anti-MPO Abs in mice. The MPO_409–428 epitope has a minimum immunogenic core region of 11 amino acids, MPO_415–426, with several critical residues. ANCA-activated neutrophils not only induce injury but lodged the autoantigen MPO in glomeruli, allowing autoreactive anti-MPO CD4⁺ cells to induce delayed type hypersensitivity-like necrotizing glomerular lesions. These studies identify an immunodominant MPO T-cell epitope and redefine how effector responses can induce injury in MPO-ANCA–associated microscopic polyangiitis.