In an attempt to understand the molecular factors underlying squamous cell carcinogenesis in HPV-infected oral and cervical tissues, we examined the Sp3-dependent cytokeratin expression in HPV-positive CaSki cells. Two sets of cytokeratins were examined: the simple epithelial CK 7, 8, 18, 19, and 20, which are generally expressed in simple epithelia and CK4, 10, 13, and 17, which are expressed in squamous epithelia. Two additional CK pairs, i.e. CK6/CK16 and CK4/CK13 were analyzed as controls of the proliferation/differentiation cell status, respectively. We report that Sp3 gene silencing specifically hits CK18 and CK19, which are markers of oral and cervical squamous tumors. These data may be of help in immunopathological definition of squamous carcinogenesis.