Severe eosinophilic asthma is characterized by chronic airway inflammation, oxidative stress and elevated proinflammatory cytokines, especially IL-5. Mepolizumab and benralizumab are both humanized IgG antibodies directed against IL-5 signaling, directly acting on eosinophils count. Together with the complexity of severe asthma classification and to the patient selection for the targeted treatment, there is also the urgency to clarify the follow-up of therapy to identify biomarkers, in addition to eosinophils, for the optimal duration of treatment, persistence of effectiveness and safety. To this purpose, here we performed a follow-up study by differential proteomic analysis on serum samples after 1 month and 6 months of both therapies and sera from healthy patients. Statistical analysis by PCA and heatmap analyses were performed, and identified proteins were used for enrichment analysis by MetaCore software. Analysis highlights 82 differences among all considered conditions. In particular, 30 referred to benralizumab time points (T0, T1B, T6B) and 24 to mepolizumab time points (T0, T1M, T6M) analyses. t-SNE and heatmap analyses evidences as the differential serum protein profile at 6 months of both treatments is more similar to that of the healthy subjects. Among the identified proteins, APOAI, APOC-II and APOC-III are up-regulated principally after six months of benralizumab treatment, plasminogen is up-regulated after six months of both treatments and ceruloplasmin, up-regulated already after 1 month of benralizumab, become higher after 6 months of mepolizumab. By enrichment analysis, identified proteins were related to lipid metabolism and transport, blood coagulation and ECM remodelling.