Introduction <p>The association between severe asthma and obesity is well established, as higher body mass index (BMI) is associated with higher prevalence and incidence of severe asthma. Biologic agents have been recently developed for severe asthma treatment. However, the efficacy of biologic agents in patients with higher BMI is not well studied. The aim of this systematic review was to determine whether there is an association between BMI and the response to five novel biologic agents.</p> Methods <p>Our study design followed the PRISMA guidelines. A literature search was performed using the PubMed/Medline and the Scopus databases up to May 2025 for the following agents: mepolizumab, benralizumab, dupilumab, reslizumab, and tezepelumab. After meticulous screening, 21 articles were selected.</p> Results <p>Studies on mepolizumab showed that higher BMI was associated with failure to achieve clinical remission, while BMI &lt; 30&#xa0;kg/m² was associated with better clinical outcomes. Regarding benralizumab, significant improvements were observed in respiratory symptoms and reductions in annual asthma exacerbation rate for patients with BMI ≤ 35&#xa0;kg/m² but not for patients with BMI &gt; 35&#xa0;kg/m². One study about dupilumab describes it as equally effective across all BMI levels. Reslizumab appears to be effective across different BMI levels; however, effectiveness seems to decrease in patients with high BMI. Regarding tezepelumab, no study was found.</p> Conclusions <p>Biologic agents are effective treatments for severe asthma, although mepolizumab, benralizumab, and reslizumab appear to have better results in patients with lower BMI. Dupilumab appears to be equally effective across all BMI categories, while no data are available for tezepelumab. More studies in patient populations with severe asthma and comorbid obesity are needed to evaluate the effectiveness of biologic therapies in this specific category of patients.</p> Trial registration <p>Registration and protocol: PROSPERO CRD42024609708.</p>