Severe asthma affects between 5 and 10% of patients with asthma worldwide and requires best standard therapies at maximal doses. A subgroup of patients remains refractory to all treatments. We describe two case reports with severe allergic asthma who progressively worsened over the years despite the best therapy. The patients were first treated with omalizumab, which was completely ineffective, and then with bronchial thermoplasty (BT), again without clinical benefit. Since our patients met the AIFA criteria for inclusion in mepolizumab treatment, a therapy with this anti-IL5 biological agent was initiated. In the first case (a 53-year-old female), after the second mepolizumab administration, symptoms improved progressively, with a reduction in the number and severity of exacerbations, so the patient could finally be discharged from hospital. At follow-up, it was possible to reduce oral corticosteroids and continuing with inhaled corticosteroids/long-acting beta-agonists and montelukast. The patient had only one exacerbation/year. Symptom control and quality of life improved significantly. In the second case report (a 55-year-old male), after the sixth mepolizumab administration, symptoms improved progressively, with a reduction in the number and severity of exacerbations. At follow-up, it was possible to reduce and stop oral corticosteroids, continuing with inhaled therapy and montelukast. Symptom control and quality of life improved significantly.These are the first cases of patients unresponsive to sequential omalizumab and BT but with good and prolonged clinical response to mepolizumab. Both cases suggest that also after the failure of two consecutive third-line treatments, a third treatment (mepolizumab) should be attempted.