Efforts have been made to identify factors influencing clinical response in patients with atopic dermatitis (AD) treated with dupilumab. A retrospective single-center observational study was carried out by analyzing data from 492 patients aged 12 years and older with moderate-to-severe AD. The study aimed to identify baseline demographic and clinical factors that could predict the achievement of a mild level of disease, i.e., an Eczema Area and Severity Index (EASI) ≤ 7, within 4 weeks from dupilumab initiation. Classic, generalized lichenoid and inflammatory phenotypes compared with a nummular eczema phenotype (OR = 6.9, 95% CI 2.04–23.48 and OR = 4.22, 95% CI 1.22–14.66, respectively) and a baseline EASI ≤ 24 and between 24–29, compared with a baseline EASI ≥ 29 (OR = 3.1, 95% CI 1.81–5.41 and OR = 1.8, 95% CI 1.05–3.07, respectively), were found to be predictive factors of early response to dupilumab, highlighting the importance of early biological treatment of AD.