Background. In this paper, we report a case of primary squamous cell carcinoma of the endometrium (PSCCE) with immunohistochemical and molecular study to evaluate the phenotype and to define the etiopathogenesis of this tumor. Case history. A 72- year- old woman was admitted to the Department of Obstetric and Gynecology for weight loss and pelvic mass. Abdominal ultrasonography disclosed the abdominopelvic mass with solid, cystic, and calcified areas. The patient underwent exploratory laparotomy. Intraoperative findings showed an enlarged uterus with perforation of its wall. The surface of omentum was covered with small white nodules. Pathological examination showed features of PSCCE. Immunohistochemical analysis with antibodies for estrogen and progesterone receptors disclosed negativity of neoplastic elements. Immunostaining with p53 tumor- suppressor protein showed the mutation of p53 tumor- suppressor protein as a strong nuclear positivity. Molecular study by polymerase chain reaction (PCR) amplification of tumor DNA did not show any signal for human papilloma virus (HPV) DNA. Conclusion. In summary, unlike the example reported in the literature by others, in the present case we demonstrated that PSCCE is not due to HPV infection, but probably to other pathogenetic mechanisms, which cause a mutation of p53 tumor- suppressor gene. Thus, it is reasonable to conclude that both HPV infection and unclear carcinogenic factors, responsible of p53 tumor- suppressor gene mutation, may cause PSCCE. Background. In this paper, we report a case of primary squamous cell carcinoma of the endometrium (PSCCE) with immunohistochemical and molecular study to evaluate the phenotype and to define the etiopathogenesis of this tumor. Case history. A 72- year- old woman was admitted to the Department of Obstetric and Gynecology for weight loss and pelvic mass. Abdominal ultrasonography disclosed the abdominopelvic mass with solid, cystic, and calcified areas. The patient underwent exploratory laparotomy. Intraoperative findings showed an enlarged uterus with perforation of its wall. The surface Immunohistochemical analysis with antibodies for estrogen and progesterone receptors published negativity of neoplastic elements. Immunohistochemical analysis with antibodies to p53 and tumor suppressor protein showed the mutation of p53 tumor-suppressor protein as a strong nuclear positivity. Molecular study by polymerase chain react In (PCR) amplification of tumor DNA did not show any signal for human papilloma virus (HPV) DNA. Conclusion. In summary, unlike the example reported in the literature by others, in the present case we demonstrated that PSCCE is not due to HPV infection, but probably to other pathogenetic mechanisms, which cause a mutation of p53 tumor-suppressor gene.