Because of the possible role of matrix metalloproteinases (MMP) and the epidermal growth factor receptor (EGFR) in the Pox virus dissemination within epithelia, the aim of this study was to compare the expression of MMPS, of specific inhibitors (TIMP) and of the EGF receptor (EGFR) in skin and lungs from Pox virus infected sheep (n = 15) with tissues from healthy sheep (n = 5) by immunohistochemistry. Hypertrophy, hyperplasia, degeneration and necrosis were found in damaged tissues and were associated with epithelial hyperkeratosis and acanthosis. Numerous sheep pox Cells (cellules claveleuses), characteristic of the pox virus infection, eventually containing cosinophil intra-cytoplasm inclusions, were frequently seen in the skin. Compared to normal tissues. the MMP-1, 7, 9 and EGFR immunoreactivity was markedly decreased whereas the MMP-2, 3 and TIMP-1 immunolabeling was stronger in tissues front Pox infected sheep. The present study showed that sheep pox virus infection call affect both epidermal and dermal component of the skin, with extracellular matrix disorganisation, leading to the altered pathway of the expression of the NIMP and then inhibitors and of EGFR.