Hypereosinophilic syndrome (HES) is a rare multisystem disease that predominantly includes skin with severe and persistent itching. A lack of understanding about the pathological condition and mechanism of dermatosis caused by HES hinders its treatment. In the present study, we applied a quantitative proteomics approach to characterize the cellular responses of skin tissue to idiopathic HES (IHES) at the proteome level. We identified hundreds of skin tissue proteins that were differentially expressed between IHES patients and healthy individuals. IHES patients display severely damaged microenvironment, including extracellular matrix (ECM) organization and disassembly, immune disorders, decreased metabolic capacity, and susceptibility to microbial infection. Moreover, there was abnormal proliferation of basal epidermal stem cells, which was closely related to high expression of the epigenetic regulator, histone deacetylase 2, providing mechanistic insight into the abnormal epidermal thickening of IHES skin tissues. Overall, our study provides a comprehensive framework for a system-level understanding of IHES-induced dermatosis (IHESiD) tissues at the protein and cell pathway levels. Our findings may facilitate a new approach to diagnosis and treatment to alleviate skin clinical symptoms, monitor the activity of IHES, and determine therapeutic effects. (C) 2020 Elsevier Inc. All rights reserved.