Abstract: The XRCC1 gene promotes the efficiency of the DNA repair process and a deletion or modification of this gene appears to result in lethal phenotypes, as we have investigated this hypothesis in this study. It was found that Arg280His variant, was associated with increased risk of head and neck cancer [OR = 2.11, 95% CI, 1.28-3.46) in smokers as compared to nonsmokers. The frequency of Arg/Arg polymorphisms was higher in the smokers (64.82%) and nonsmokers (69.03%) compared to the cancer patients (46.6%) suggesting that this particular mutation may not be adverse genotype, whereas the heterozygous variant (Arg/His) and homozygous variant His/His were more frequent in the patients than in the smokers and nonsmokers suggesting that these genotypes were high risk groups. The distribution of Arg/Arg, Arg/Gln and Gln/Gln genotypes at the Arg399Gln site for nonsmokers was 44.6, 43.22 and 6.45% and for smokers it was 47.5, 43.4 and 8.96%, respectively. Individual who smoked >15 years and carried the codon 280 Arg/His genotype had an OR = 2.30, 95% CI, 1.01-5.30 and who smoked less than 15 years had an OR = 1.64, 95% CI, 0.78-3.46, these results suggested that the codon Arg280His genotypes were associated with high risk of head and neck cancers in heavy smokers.