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Background: One third of patients with severe asthma who are eligible for treatment with omalizumab may also qualify for mepolizumab treatment and vice-versa. Aim: To compare the clinical efficacy of the two biologics in patients with severe asthma with both allergic and hyper-eosinophilic patterns. Materials and Methods: Patients on treatment with omalizumab (n=57) or mepolizumab (n=63) between 2008 and 2018 with positive skin prick test and eosinophils > 150 were enrolled. Propensity score matching was performed, using a multivariable logistic regression model with the following key variables: age, sex, BMI, disease duration, ACT, eosinophils, oral steroid use. 90 matched pairs of patients treated with omalizumab or mepolizumab were retrieved. Number of exacerbations, asthma control test (ACT), eosinophils, FEV1 and corticosteroid use were recorded at baseline (b), and after 52 weeks (52w). Results: Both treatments were effective in improving FEV1, asthma exacerbations, ACT and OCS usage after 52 w. Indeed, mepolizumab significantly reduced eosinophils and OCS usage compare to omalizumab, as shown in Table 1. Conclusion: Omalizumab and mepolizumab showed similar beneficial effects, with mepolizumab showing a significant pronounced effect in OCS usage and eosinophils reduction in real-world settings.