Patients with severe OCS-dependent asthma can be considered a subgroup of asthma patients with severe disease and great risk of complications, related to chronic OCS use. The introduction of biological drugs has represented a turning point in the therapeutic strategy for severe asthma, offering a valid alternative to OCS. Benralizumab, like other anti-IL-5 agents, has been shown to reduce exacerbations and OCS intake/dosage and improve symptom control and lung function. While these findings have also been confirmed in real-life studies, data on long-term efficacy are still limited. Methods: In this retrospective study, we evaluated the effects of 2 years of treatment with benralizumab on 44 patients with OCS-dependent severe asthma by analyzing clinical, biological and functional data. Results: After 2 years of benralizumab, 59.4% discontinued OCS and patients who continued to use OCS had their mean dose reduced by approximately 85% from baseline. Meanwhile, 85% of patients had their asthma well-controlled (ACT score > 20) and had no exacerbations, and 41.6% had normal lung function. Conclusions: Our findings support the long-term effectiveness of benralizumab in severe OCS-dependent asthma in a real-life setting, suggesting potential reductive effects on costs and complications such as adverse pharmacological events.