Down syndrome (DS) is the most common chromosomal disorder and a major cause of mental retardation. Down syndrome phenotype is complex and may present a combination of dysmorphic features, congenital heart disease and immunological deficiency. Psoriasis it has been noted to be 0.5%-8% in patients with DS and numerous factors can limit the use of therapeutic options, in particular long-term organ-specific toxicity, and the risk of opportunistic infections. It is still debated whether the use of biologics in the treatment of DS-related psoriasis is safe. We have valuated the efficacy and safety of ustekinumab treatment in-patient with DS suffering from plaque type psoriasis. A 31-year-old patient suffering from plaque type psoriasis since the age of 14, showed a PASI score of 12 after the failure of anti-TNF agents. We switched the patient to ustekinumab treatment at the standard dose of 45 mg subcutaneously initially and 4 weeks later, followed by 45 mg every 12 weeks. The patient showed a significant improvement of the PASI score already after 4 weeks of treatment and further improvements were observed throughout the treatment. We report the first case of DS-correlated psoriasis patient treated for a long-term period with various biologics, showing a satisfactory safety profile undergoing treatment. In our experience, ustekinumab has demonstrated a high efficacy, relatively rapid onset of action, favorable safety profile, and can be considered a good treatment option even after failure to respond to other biologic therapies in patient with DS.