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ABSTRACT Background Aim Methods Results Conclusion Blocking IL‐13 is highly efficacious in patients with Th2‐biased atopic dermatitis (AD), and recent clinical data have highlighted that targeting the T cell costimulatory molecules OX40 and OX40L (TNFSF4) holds promise for future treatment of AD.We asked whether targeting another T cell costimulatory molecule, CD30L (TNFSF8), might also be a possible treatment option in AD.Single‐cell RNA‐seq data from human AD skin lesions was analyzed to identify pathogenic IL‐13‐ or IL‐22‐producing T cells and assess expression of CD30 and its ligand in comparison to OX40 and its ligand. Additionally, a murine model of AD with repetitive exposure to house dust mite allergen was used to compare neutralizing antibodies against CD30L with those against IL‐13 or OX40L.Analysis of several scRNA‐seq datasets from skin lesions of AD patients showed that transcripts for CD30 or CD30L were found expressed with OX40 or OX40L in the primary T cell populations that also expressed mRNA for IL13 and/or IL22. Suggesting that this could be therapeutically relevant, mice treated prophylactically with a blocking CD30L antibody were protected from developing maximal allergen‐induced AD features, including epidermal and dermal thickening, immune cell infiltration, and expression of AD‐related genes, similar to mice treated with a blocking IL‐13 antibody. Moreover, therapeutic neutralization of CD30L in mice with experimental AD also reduced all of the pathological skin lesion features to a comparable extent as blocking OX40L.These data suggest that targeting the CD30–CD30L axis might hold promise as a future therapeutic intervention in human AD, similar to targeting the OX40–OX40L axis. [ABSTRACT FROM AUTHOR]