Atopic dermatitis (AD) is a chronic skin condition affecting an increasing number of children and adults whose quality of life is impacted by chronic itch and pain. It is characterized by an altered epidermal barrier, skin inflammation, and skin microbiome dysbiosis particularly over-colonization of Staphylococcus aureus. The efficacy and tolerance of a cream containing a S. aureus-targeting technology (endolysin) was assessed in an open-label, two-week study in children and adults with mild-to-moderate atopic dermatitis. A total of 43 patients ranging from 7 months to 57 years old were included and all patients finished the study without any tolerance problem. Disease severity, measured with SCORAD, quickly reduced by 43% in 7 days and by 68 % in 14 days. The benefit was perceived by the whole panel with a marked improvement in overall QoL. This study shows the efficacy of a highly specific S. aureus-targeted technology in alleviating symptoms and improving QoL in children and adults with atopic dermatitis. It could also be beneficial in reducing and preventing flares in subjects with S. aureus load due to its good tolerance and specific action. J Drugs Dermatol. 2021;20(12):1323-1328. doi:10.36849/JDD.6363.