<b><i>Background:</i></b> Localization of atopic dermatitis (AD) in exposed areas such as the hands, head, and neck has been considered as a negative factor impacting on dupilumab response, although a comparison of exposed versus unexposed areas is not currently available. <b><i>Objectives:</i></b> The aim of this study is to evaluate the clinical response to dupilumab depending on the presence or persistency of AD skin manifestations in specific body areas. <b><i>Methods:</i></b> The study retrospectively collected clinical and demographic data of adult patients affected by moderate to severe AD. Based on the anatomical sites involved, 5 subcohorts of patients were identified. <b><i>Results:</i></b> A total of 41 patients were included in the study. Disease amelioration was detected during the study period, although baseline head/neck and hand localization was associated with a significantly lower likelihood of achieving an Eczema Area Severity Index (EASI) ≤1. In addition, patients with head/neck persistency showed a significantly lower response when compared to patients without persistency of head/neck AD in terms of both mean EASI and Dermatology Life Quality Index (DLQI) reduction. <b><i>Conclusion:</i></b> AD localization in exposed areas at the baseline and AD persistency at the head/neck may have a negative impact on certain treatment response parameters to dupilumab therapy.