CYLD is a tumor-suppressor gene mutated in the skin appendage tumors cylindromas, trichoepitheliomas, and spiradenomas. We have performed in vivo metastasis assays in nude mice and found that the loss of the deubiquitinase function of CYLD in squamous cell carcinoma (SCC) cells greatly enhances the lung metastatic capability of these cells. These metastases showed several characteristics that make them distinguishable from those carrying a functional CYLD, such as robust angiogenesis, increased expression of tumor malignancy markers of SCCs, and a decrease in the expression of the suppressor of metastasis Maspin. Restoration of Maspin expression in the epidermal SCC cells defective in CYLD deubiquitination function significantly reduces their ability to form metastases, thereby suggesting that the decrease in the levels of Maspin expression plays an important role in the acquisition of metastatic potential of these cells. In addition, we have characterized Maspin downregulation in cylindromas, trichoepitheliomas, and spiradenomas carrying functional inactivating mutations of CYLD, also providing an evidence of the correlation between impaired CYLD function and Maspin decreased expression in vivo in human tumors.