Abstract: Background and Objective: Squamous cell carcinoma of head and neck (SCCHN) is attributed by tobacco chewing and smoking which are known to cause DNA damage. Eventually such damage if get fixed as mutation can enhance the risk of SCCHN. These damaged are repaired by DNA repair protein such as MutS Homolog 3 (MSH3). Therefore, genetic polymorphisms in MSH3 gene which affect its efficiency can modulate the risk of cancer including SCCHN. The present study examined the association of MSH3 rs26279 G>A polymorphism with the risk and clinical outcome of SCCHN. Materials and Methods: One Hundred and eighty six patients of SCCHN and 188 cancer free healthy control subjects were genotyped by PCR-RFLP method. Genotypes of SCCHN patients were further correlated with their disease status including stage, grade, tumour size, metastasis and lymph node involvement. Results: The risk of developing SCCHN was 2 times more with GG genotype compared to AA genotype for MSH3 G>A polymorphism (OR = 2.61, 95% CI 1.06-6.73, p-value = 0.05). The G allele itself imparted significantly higher risk for developing SCCHN compared to A allele (OR = 1.55, 95% CI 1.08-2.26, p-value = 0.01). Variant allele genotype (AG+GG) of MSH3 G>A polymorphism were associated with the development of high staged (III+IV) and large sized tumour (T3+T4). Compared to the common allele genotype (AA) the risk of developing high staged and large sized tumour were 2 times more with variant allele genotype (OR = 2.34, 95% CI = 1.19-4.58, p-value = 0.02 and OR = 2.14, 95% CI 1.32-4.40, p-value = 0.006, respectively). Conclusion: Result from the present study suggested that MSH3 rs26279 G>A polymorphism cannot only modify the risk for developing SCCHN but also the clinical status of tumour in SCCHN patients.