The aim of this study was to describe 40 cases of acquired oral syphilis (AOS) and to discuss the distribution of demographic characteristics, clinical features, and differential diagnosis of the disease. A retrospective study was conducted covering a 17-year period at a single institution in southern Brazil. Moreover, a literature review was performed through a search of the PubMed database for articles on AOS published between 1955 and March 2018. Data were analyzed descriptively. The predominant group within the case series was male patients in their twenties. The vast majority of cases (92.5%) were in the secondary stage of the disease. The lips were the most commonly affected site, with greyish-white mucous patches and reddish ulcers. In the literature review, the largest number of reported cases came from North America. Male patients in the third and fourth decades of life were most affected. AOS occurred more commonly as mucous patches and ulcers on the tongue and palate. Similarities regarding the distribution by sex, age, and anatomical location were found in the present study when compared to cases reported elsewhere. Clinicians, oral pathologists, and maxillofacial surgeons should familiarize themselves with the variable spectrum of signs and symptoms of AOS in their clinical practice to improve diagnosis and management.