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In antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), the treatment of choice is either Rituximab or cyclophosphamide in combination with steroids. In less extended forms of AAV, however, less toxic regimens are being used.In the current review, we will focus on the role of one of these less toxic regimens, that is trimethoprim–sulfamethoxazole monotherapy as induction treatment or as maintenance therapy in AAV.A substantial portion of patients with active granulomatosis with polyangiitis (GPA) limited to the upper airways can be initially controlled with trimethoprim–sulfamethoxazole (2 × 960 mg/day) monotherapy. In patients with initially a complete response, long-term control of the disease seems possible. In addition, trimethoprim–sulfamethoxazole (2 × 960 mg/day) maintenance therapy is an option for patients with GPA that have been proven to be frequent relapsers. The mechanism by which trimethoprim–sulfamethoxazole works in GPA is at present unknown. Suppression of Staphylococcus aureus carriage and/or anti-inflammatory mechanisms has been postulated.Trimethoprim–sulfamethoxazole may be considered as a safe initial treatment in GPA patients with disease localized to the ear, nose, and throat region. Furthermore, trimethoprim–sulfamethoxazole in a dose of 2 × 960 mg/day may be used to prevent relapses in GPA.