Background: Head and neck squamous cell cancer” (HNSCC) is a term collectively describes the malignant tumours of oral cavity, pharynx and larynx. Globally, the total burden of HNSCC is estimated to be around 22 millions and males outnumber females by 4.1 to 2. Folate Metabolic pathway is complex and crucial process that contributes to folate levels and DNA methylation. The genes behind the enzymes in the pathway are polymorphic in nature and a specific combination of genetic variants may implicates differential susceptibility to different cancers. Methylenetetrahydrofolate reductase (MTHFR), a key enzyme for intracellular folate homeostasis and metabolism provides methyl groups for the methylation of homocysteine to methionine. Aim: The present study aimed to identify genetic variants of MTHFR C677T (rs1801133) and MTHFR A1298C (rs1801131) among HNSCC patients and controls, gene – environment interactions in North Coastal Andhra Pradesh. Methods: A total of 220 samples (110 HNSCC patients and 110 controls) were included in the study and genotyping was accomplished by using PCR - RFLP technique and analyzed by SPSS. Results: The chi square p values revealed that MTHFR (C677T) polymorphism has association with HNSCC and MTHFR (A1298C) polymorphism does not shows association with HNSCC. For MTHFR (C677T) polymorphism, the odds ratio p value of TT genotype and CC genotype of MTHFR (A1298C) was found to be statistically significant. Conclusions: In conclusion, the MTHFR C677T (rs1801133) polymorphism shows association and A1298C (rs1801131) polymorphism does not shows association with HNSCC.