A significant proportion of patients with oral squamous cell carcinoma do not have the typical risk factors of smoking and alcohol consumption in their medical history. Clinical and immunohistochemical studies have shown that patients with oral squamous cell carcinoma who have never smoked or drunk alcohol are more likely to be female and older at the time of diagnosis. In addition, this type of patient has a more frequent history of oral potentially malignant disorders and a better prognosis. There are also differences in the site of origin of the carcinoma between never-smokers/never-drinkers and smokers/drinkers. In addition, we were able to show that oral squamous cell carcinoma in never-smokers/never-drinkers has an independent immunologic microenvironment. These results may help to improve the treatment of oral squamous cell carcinoma in never-smokers/never-drinkers. The aim of this study was to investigate the clinical, histopathologic, and immunologic differences of oral squamous cell carcinoma of never-smokers/never-drinkers and smokers/drinkers. Immunohistochemical staining for CD4, CD8, FoxP3, CD1a, and p16 was performed in 131 oral squamous cell carcinomas from smokers/drinkers and never-smokers/never-drinkers. Associations of smoking/drinking status with clinicopathologic data, immunohistochemical antibody expression, and survival were examined. Oral squamous cell carcinoma in never-smokers/never-drinkers was associated with the female gender (p < 0.001). Never-smokers/never-drinkers were older at diagnosis than smokers/drinkers (p < 0.001). Never-smokers/never-drinkers had more tumors in the maxilla, mandible, and tongue (p < 0.001). Pre-existing oral potentially malignant disorders appeared to be more common in never-smokers/never-drinkers (p < 0.001). Perineural invasion was more common in smokers/drinkers (p = 0.039). Never-smoking/never-drinking was associated with better overall survival (p = 0.004) and disease-specific survival (p = 0.029). High CD4+ T cell infiltration was associated with never-smoking/never-drinking (p = 0.008). Never-smokers/never-drinkers also showed increased CD8+ T cell infiltration (p = 0.001) and increased FoxP3+ Treg infiltration (p = 0.023). Furthermore, the total group of tumor-infiltrating lymphocytes was associated with never smoking/never drinking (p = 0.005). To conclude oral squamous cell carcinoma of the neversmokers/never-drinkers appears to be a distinct type of tumor, as it appears to have unique clinical and pathologic features and a more immunogenic microenvironment.