<b><i>Background:</i></b> It is not clear whether mepolizumab is differently effective in allergic and nonallergic severe eosinophilic asthmatics (SEA) in real life. <b><i>Objective:</i></b> We tested mepolizumab effectiveness in allergic/nonallergic SEA in real life. A strict criterion to identify the 2 phenotypes was used. <b><i>Method:</i></b> We retrospectively considered 134 consecutive patients divided into allergic, with a positivity to at least 1 allergen to prick tests and/or IgE values ≥100 UI/mL (severe allergic eosinophilic asthma [SAEA]; <i>n</i>: 97–72.4%), and nonallergic, with no prick test results and normal IgE levels &#x3c;100 UI/mL (severe nonallergic eosinophilic asthma [SNAEA]; <i>n</i>: 37–27.6%). They had taken mepolizumab for at least 6 months. <b><i>Results:</i></b> After 10.9 ± 3.7 months, improvements in FEV₁%, FEF_25–75%, exacerbation numbers, blood eosinophil (BE) counts, fractional exhaled nitric oxide (FENO) (ppb), percentages of patients that stopped/reduced short-acting β2-agonists (SABAs) or oral corticosteroid (OC), observed after treatment, were similar in both groups. Only Asthma Control Test (ACT) increases were higher in SNAEA (8 [5–9]) than in SAEA (5 [2.5–8.5]; <i>p</i> = 0.016). However, no differences were found after treatment in percentages of subjects with ACT ≥20, as well as with FEV₁ &#x3e;80%, FEF_25–75 &#x3e;65%, exacerbations ≤2, BE &#x3c;300 cells/µL, and FENO &#x3c;25 ppb between SAEA and SNAEA. Besides, no significant relationships were found, comparing SNAEA with SAEA, for FEV₁% (β = −0.110; <i>p</i> = 0.266), FEF_25–75% (β = −0.228; <i>p</i> = 0.06), BE counts (β = −0.012; <i>p</i> = 0.918), FENO (β = 0.234; <i>p</i> = 0.085), ACT (β = 0.046; <i>p</i> = 0.660), and exacerbations (β = −0.070; <i>p</i> = 0.437). No different associations between lung function and SNAEA occurrence when compared to SAEA condition (FEV₁ &#x3e;80%: OR = 1.04 [95% CI: 0.43–2.55], <i>p</i> = 0.923; FEF_25–75 &#x3e;65%: OR = 0.41 [95% CI: 0.08–2.03], <i>p</i> = 0.272) were detected. Neither all other parameters, such as ACT &#x3e;20 (OR = 0.73 [95% CI: 0.32–1.63], <i>p</i> = 0.440), presence of exacerbations (OR = 1.35 [95% CI: 0.55–3.27], <i>p</i> = 0.512), SABA discontinuation (OR = 1.16 [95% CI: 0.40–3.39], <i>p</i> = 0.790), and OC cessation/reduction (OR = 3.44 [95% CI: 0.40–29.27], <i>p</i> = 0.258), were differently associated with 1 or the other phenotype. <b><i>Conclusion:</i></b> Mepolizumab can be considered as a valid therapeutic choice for either allergic or nonallergic SEA in real life.