<strong>Objective</strong>: Oral squamous cell carcinoma (OSCC) with its poor survival rates and rising number of incidences arises through several etiological factors including environmental, genetic and epigenetic alterations. Several studies have established an association between cancer susceptibility and polymorphisms of methylenetetrahydrofolate reductase (MTHFR), the key enzyme involved in folate metabolism and, therefore in DNA synthesis, methylation and repair. The aim of the present study was to establish any association between MTHFR A1298C variants and alcohol and/or tobacco consumption, gender or age in respect to clinical histopathological parameters, and the risk of OSCC development in the Turkish population. <br> <strong>Material and Method</strong>: MTHFR A1298C genotyping in 107 OSCC patients and 107 cancer-free healthy controls was performed using the PCR-RFLP method. <br> <strong>Results</strong>: The study groups were age-matched with higher frequencies in the male gender. In the patients group, the distribution of MTHFR A1298C variants was not significant. Smoking was not found to be a risk factor: in non-smokers the frequency of the MTHFR A1298 allele was higher than the 1298C allele, and the A1298 allele carriers possessed moderately or well differentiated tumors with a diameter of <4 cm. However, these associations were not detected in smokers. <br> <strong>Conclusion</strong>: The present study alone did not demonstrate any association between the MTHFR A1298C polymorphism and the risk of OSCC in the Turkish population, however the prognosis of OSCC may be influenced by MTHFR A1298C variants.