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Little is known about the efficacy and safety of the anti-interleukin 5 monoclonal antibody mepolizumab (MPZ) in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in real-life. We thus evaluated disease activity, damage and disease-related complications in 14 patients with EGPA receiving MPZ for refractory disease for a median time of 16 months in comparison with up to five years before MPZ start. Asthma exacerbation rates, the Birmingham Vasculitis Activity Score and corticosteroid dosage decreased during MPZ (p < 0.001, p < 0.001 and p = 0.001, respectively). Five patients could discontinue prednisone. Infection rates were higher during MPZ (p < 10–6), but no rises in hospitalizations, asthma exacerbations or damage accrual were observed. Real-life data confirm the effectiveness of MPZ in refractory EGPA with active asthma. Higher infections rates are in line with other studies and might be due to relative overreporting secondary to increased visit frequency, although a pharmacological effect could not be ruled out.