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Down syndrome (DS) is the most common chromosomal disorder; several dermatological conditions are common in these patients; among them, psoriasis and atopic dermatitis can be frequently encountered. From 2017 to today, we retrospectively identified 4 adults and 3 under 18-year-old patients treated with biological drugs, from our research database. The first endpoint of this study was to evaluate whether the biological drugs work in these special population, and a secondary endpoint was to evaluate any loss of efficacy or any side effects during follow-up. All patients were treated with biological drugs experience resolution of their psoriasis. Mean PASI (Psoriasis Area Severity Index), BSA (Body Surface Area) and DLQI (Dermatology Life Quality Index) at baseline were 20, 16.5 and 25. At week 4, mean PASI, BSA and DLQI decreased, respectively, to 8, 6 and 12, while at week 24, mean values were, respectively, 3, 1.3 and 1. The patients that started therapy earlier, at week 52, do not have signs of recurrence and side effects. We highlighted that no official guidelines exist to approach these patients, from a literature evaluation the most employed drugs are anti-TNFα and in particular adalimumab. In our experience, the new anti-interleukin drugs seem to be well-tolerated, with no sides effect, good compliance and no loss of efficacy.