The aims of this study were to assess the expression levels of three proteins involved in apoptosis--Bcl-2, Bcl-X, and Bax--and evaluate their relationship with clinicopathologic features and survival in oral squamous cell carcinoma (OSCC). Immunohistochemistry was used to evaluate protein expression in 53 primary OSCCs treated by radical surgery with free margins at a single institution in 1999. Histologic specimens were graded and analyzed for perineural invasion, lymphocytic infiltrate, and pattern of invasion. Digital image analysis was performed to quantify immunostaining. Survival was analyzed using the Kaplan-Meier method and Cox's proportional hazard model. Cancer-specific 5-year survival (CSS) was 61% (56% overall survival (OS), and 51% disease-free interval (DFI)). Kaplan-Meier analysis identified pathologic stage (p=0.0007, log-rank test, OS), negative nodes status (pN) (p<0.0001, log-rank test, OS), presence of lymphocytic infiltrate (p=0.0084, log-rank test, OS), and high Bax expression (p=0.025, log-rank test, OS) to each be associated with both better OS and CSS. Tongue tumors (p=0.0179, log-rank test), worst pattern of invasion (p=0.0293, log-rank test), lack of lymphocytic infiltrate (p=0.0328, log-rank test), perineural invasion (p=0.0448, log-rank test), poorly differentiated tumors (p=0.0318, log-rank test), and low Bcl-X expression (p=0.044, log-rank test) were all associated with a low DFI. Cox regression found pN, lymphocytic infiltrate, and Bax expression to be independent prognostic factors for OS and CSS, whereas lymphocytic response and tongue tumors were predictors of DFI. Bcl-2 expression emerged as an independent marker of favorable CSS. Lymphocytic infiltrate was the most meaningful histopathologic parameter in survival analysis, whereas expression of Bcl-2 family members seems to be an important marker of a favorable prognosis in OSCC.