Background: Previous studies have shown that topical corticosteroid (TCS) use induces structural abnormalities of the stratum corneum (SC), resulting in permeability barrier disruption. It is well-known that epidermal barrier perturbation induces a cytokine cascade, leading to cutaneous inflammation. Accordingly, we hypothesize that barrier disruption caused by long-term TCS therapy may trigger a cutaneous cytokine cascade, which plays an important role in withdrawal dermatitis (WD) following discontinuation of TCS. The objective of this study was to elucidate the possible mechanism of WD. Methods: Hairless mice were treated once daily with 0.064% betamethasone dipropionate ointment for 6 weeks. After discontinuation of TCS, we examined the transepidermal water loss (TEWL), SC lipids and expression of the cytokines interleukin 1-alpha (ILI-alpha) and tumor necrosis factor-alpha (TNF-alpha) and their downstream signaling pathway in the following 2 weeks. Results: We observed upregulation of ILI-alpha, TNF-alpha., inhibitor of nuclear factor kappa-B kinase subunits alpha and beta (IKK1, IKK2) and nuclear factor kappa-B (NF-kappa B) in the epidermis, accompanied by a significantly higher TEWL after TCS cessation. These cytokines gradually disappeared with concomitant normalization of TEWL after 1 week. Only negligible amounts of the aforementioned cytokines were observed in the dermis. Furthermore, concurrent application of petrolatum during TCS treatment decreased barrier impairment and production of cytokines. Conclusion: An epidermis-derived cytokine cascade was observed following TCS-induced barrier disruption, which is similar to that from permeability barrier insults by acetone or tape stripping. The study suggests that concurrent application of skin care products during TCS treatment improves barrier homeostasis, and should become a standard practice to alleviate TCS-induced WD. Copyright (C) 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.