<b><i>Background:</i></b> Dupilumab, a monoclonal antibody inhibiting the signaling pathway of IL-4/IL-13, was shown to be safe and effective in the treatment of moderate/severe atopic dermatitis (AD) in several clinical trials and real-life experiences, with only a small percentage of patients showing to be resistant or to lose disease control. <b><i>Objectives:</i></b> In this study, we investigated the effectiveness and safety in combining dupilumab with systemic agents or phototherapy in patients experiencing an inadequate response to dupilumab. <b><i>Methods:</i></b> This retrospective, monocentric, observational study consecutively included patients aged &#x3e;18 years, with moderate-severe AD, under treatment with dupilumab. In this cohort of patients, we analyzed data of subjects who experienced an inadequate response to dupilumab, even when combined with topical corticosteroids, and for whom an additional systemic treatment or phototherapy was combined to dupilumab. <b><i>Results:</i></b> In this study, we included a total population of 69 patients treated with dupilumab. In 12/69 patients (17.4%) showing an inadequate response to dupilumab, a combined treatment consisting of dupilumab plus methylprednisolone (<i>n</i> = 5), cyclosporine (<i>n</i> = 4), methotrexate (<i>n</i> = 2), or narrow band-UVB (<i>n</i> = 1) was administered. Overall, after 8 weeks of combined therapy, the majority of patients (11 of 12) obtained an improvement of signs and symptoms of AD. Patients treated with combined therapy did not experience any adverse events, neither did they withdraw treatment because of the occurrence of adverse events. <b><i>Conclusions:</i></b> This study suggests that the combination of dupilumab with a conventional drug or phototherapy may represent a valid therapeutic choice, maintaining a good safety profile in AD patients recalcitrant to dupilumab monotherapy.