Comparative Analysis of Oral and Oropharyngeal Mucosal Lesions of American Tegumentary Leishmaniasis and Other Infectious Granulomatous Diseases and Squamous Cell Carcinoma

American tegumentary leishmaniasis (ATL) and other infectious granulomatous diseases (IGDs) may present with oral/oropharyngeal mucosal lesions (OOPML). IGD-OOPML can result from fungal, parasitic, or bacterial infections, and squamous cell carcinoma (SCC) represents the main differential diagnosis. ATL, other IGD, and SCC share overlapping clinical and epidemiological features, making diagnostic suspicion challenging. This study compared sociodemographic and clinical characteristics among ATL, other IGD, and SCC. Descriptive, comparative, and multivariable logistic regression analyses were performed. Among 7551 patients, 213 met inclusion criteria (83-SCC and 130-IGD). Except for smoking, which differed only between ATL and SCC, most IGD parameters were similar. Male patients predominated in all groups. SCC patients were significantly older (p < 0.001) and had a shorter median disease duration (p = 0.007). The presence of pain increased the odds of SCC-OOPML by 3.96 times (95% CI 1.97–12.51). SCC patients were more likely to present lesions in a single subsite, either the oral cavity or oropharynx. Painful, ulcerated, or exophytic lesions favored SCC diagnosis, whereas infiltrative, granular, or mulberry-like lesions, involvement of multiple subsites, or associated nasal and laryngeal lesions suggested IGDs. Although clinical differentiation remains difficult, these findings may support early diagnostic suspicion, prompt treatment, and reduced sequelae.