Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy. This retrospective study has the objective to compare the efficacy of dupilumab therapy in patients with IAD versus EAD in a real-life setting. We studied a group of 360 patients treated with dupilumab for moderate-to-severe AD of whom 49 had IAD (IgE < 200 kU/L and no history of other atopic conditions) and 311 had EAD (IgE ≥ 200 kU/L and/or history of atopy). There were no statistically significant differences in the achievement of EASI75 between IAD and EAD patients either at 16, 32, or 48 weeks (61% vs. 50%; 66% vs. 60%; and 53% vs. 65%, respectively). Similarly, there were no statistically significant differences in the achievement of EASI90 or the reduction in NRSpp, NRSsd, and DLQI at each timepoint. Additionally, mean absolute eosinophils and IgE values were significantly higher in the EAD group at all timepoints. This study confirms that dupilumab, targeting the Th2 pathway, which is known to be overexpressed in all AD phenotypes, appears to be equally effective in the two populations regardless of IgE levels.