Objective: To report the clinicopathologic features of acquired oral syphilis cases in South American countries. Materials and Methods: Clinical data were retrospectively collected from the records of 18 oral diagnostic services in Argentina, Brazil, Chile, Colombia, Venezuela, Uruguay, and Peru. Serologies of nontreponemal and treponemal tests were used for diagnosis. Results: The series comprised 339 cases of acquired oral syphilis. Secondary syphilis ranked as the most common stage (86.7%). Lesions were more frequent among males (58.0%) and young adults with a mean age of 33.3 years. Individuals aged 20–29 years were most affected (35.3%). The most commonly involved sites were the tongue (31.6%), lip/labial commissure (25.1%), and hard/soft palate (20.4%). Clinically, acquired oral syphilis usually presented as mucous patches (28.4%), papules (25.7%), and ulcers (18.1%). Skin manifestations occurred in 67.7% of individuals, while lymphadenopathy and fever were observed in 61.3% and 11.6% of all subjects, respectively. Most patients were treated with the benzathine penicillin G antibiotic. Conclusion: This report validates the spread of acquired oral syphilis infection among young adults in South America. Our directives include accessible diagnostic tools for proper disease screening, surveillance, and counselling of affected individuals, especially in low- and middle-income countries.