A long-term prospective observational safety study is essential to fully characterize the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset.We present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema to assess the long-term safety risk of these therapies in a routine clinical care setting.We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or anothersystemic immunomodulating agent for their atopic eczema will be included. The primary endpoint is the incidence of malignancies (excluding non-melanoma skin cancer) compared between the treatment groups. Secondary endpoints include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia.This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. This article is protected by copyright. All rights reserved.