There are many controversies in head and neck granulomatosis with polyangiitis (HN-GPA). Diagnostic/therapeutic regimens vary due to limited knowledge about the special properties of HN-GPA. 28 patients were diagnosed with GPA accordingly. Anti-neutrophil-cytoplasmatic-antibody (ANCA), anti-peroxidase-antibody (anti-PR3) and biopsies were performed for all patients and set into clinical context. 14 patients had sinonasal symptoms. Otological (n = 8) and laryngeal (n = 2) symptoms were usually associated with complex disease activity. Pulmonary and/or renal impairment was present in 14 patients at the time of diagnosis and developed in a further nine patients within 1 year. 21 patients with systemic disease displayed elevated ANCA/anti-PR3. In contrast, those with persistent isolated HN manifestations (n = 6) lacked auto-antibodies. These patients underwent multiple biopsies to diagnose GPA. Interestingly, five patients without clinical HN manifestations but elevated auto-antibodies were identified by nasal "blind" biopsy. Clinical examination, auto-antibody testing, and histology are effective diagnostic tools in HN-GPA. Histological diagnosis remains the gold standard in patients with persistent isolated head and neck manifestations but missing auto-antibodies. Based on our findings, we suggest early and sufficient systemic therapy for all HN-GPA. Nasal mucosal "blind" biopsy should be performed in patients with elevated auto-antibodies but lacking clinical head and neck manifestations.