Background: Patients with atopic dermatitis (AD) are susceptible to several viruses, including herpes simplex virus (HSV). Some patients experience 1 or more episodes of a severe skin infection caused by HSV termed eczema herpeticum (EH). There are numerous mouse models of AD, but no established model exists for EH. Objective: We sought to establish and characterize a mouse model of EH. Methods: We infected AD-like skin lesions with HSV1 to induce severe skin lesions in a dermatitis-prone mouse strain of NC/Nga. Gene expression was investigated by using a microarray and quantitative PCR; antibody titers were measured by means of ELISA; and natural killer (NK) cell, cytotoxic T-cell, regulatory T-cell, and follicular helper T-cell populations were evaluated by using flow cytometry. The role of NK cells in HSV1-induced development of severe skin lesions was examined by means of depletion and adoptive transfer. Results: InoculationofHSV1inducedsevereerosiveskinlesionsin eczematousmice, which had an impaired skinbarrier, butmilder lesionsinsmallnumbersofnormalmice. Eczematousmiceexhibited lowerNKcellactivitybutsimilarcytotoxicT-cellactivityand humoralimmuneresponsescomparedwithnormalmice. Theroleof NKcellsincontrollingHSV1-inducedskinlesionswasdemonstrated byexperimentsdepletingortransferringNKcells. Conclusion: A murine model of EH with an impaired skin barrier was established in this study. We demonstrated a critical role of defective NK activities in the development of HSV1induced severe skin lesions in eczematous mice.