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Oral squamous cell carcinoma (OSCC) is one of the most common cancers in geographic regions in Asia where betel quid (BQ) chewing is prevalent. Furthermore, history of alcohol drinking, lower level of nodal metastasis, advanced stage, poor cell differentiation, and treatment failures are independent predictors of poor disease-specific survival. Due to the high frequencies of loco regional recurrence and second primary cancer, we emphasize that aggressive surgical excision, adjuvant treatments according to clinicopathological prognostic factors and close surveillance are important to the survival of OSCC patients in an area with a high prevalence of betel quid chewing and tobacco smoking. OSCC is an extremely malignant neoplasm whose prognostic factors are multiple, complex and debilitating.