The Organization for Economic Co-operation and Development approved a reconstructed human epidermis (RHE) model forin vitroskin irritation and corrosion tests as an alternative to animal testing for cosmetics, which has been banned in the European Union since 2013. However, RHE models have several limitations, such as high manufacturing costs, a loose skin barrier, and inability to simulate all cellular and non-cellular components of the human epidermis. Therefore, new alternative skin models are needed. Ex vivo skin models have been suggested as promising tools. Here, we investigated the structural similarities in the epidermis of pig and rabbit skin, a commercial RHE model (Keraskin), and human skin. To compare the structural similarity, the thickness of each epidermal layer was compared using molecular markers. Among the candidate human skin surrogates, the epidermal thickness of the pig skin was the most similar to that of human skin, followed by rabbit skin and Keraskin. Keraskin showed thicker cornified and granular layers than human skin, while rabbit skin displayed thinner layers. Moreover, the proliferation indices of Keraskin and rabbit skin were higher than those of human skin, whereas the proliferation index of the pig skin was similar to that of human skin. Some or none of the human skin barrier proteins FLG, CLDN1, and CDH1 were expressed in pig and rabbit skin, whereas all human proteins were expressed in Keraskin. Collectively, we propose ex vivo pig skin as the most suitable model for skin irritation testing because of its similarity to human skin.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43188-023-00185-1.