Syphilis, a sexually transmitted infection, has increased in incidence over the years, especially among the adult population. The oral manifestation of primary syphilis is usually characterized by a clinical course variable in which it progresses to the next stages if not treated. In this report, we present two cases of oral manifestation of primary syphilitic lesion with peculiar clinical characteristics, and we emphasize the importance of a correct diagnosis. Biopsies were needed for differential diagnosis and serological exams were requested. The histopathological analysis suggested the diagnosis and the immunohistochemistry confirmed the presence of Treponema pallidum. Antibiotic therapy was initiated with complete remission of the lesion. Therefore, a thorough anamnesis and a thorough clinical examination are essential for establishing the correct diagnosis, to begin the treatment of syphilis as soon as possible, thus avoiding the disease’s progression.