The increased prevalence of Helicobacter pylori infection and inadequate genetic research on the same, demands a genetic study among Tamil population of South India to unravel the association of NLRP3 (NLR family pyrin domain containing 3) variants with persistent H. pylori infection. This research was aimed to study the correlation between persistent H. pylori infection and influence of such genetic variants in the development of disease progression. In this study, 200 healthy volunteers and 120 H. pylori-positive cases were screened for two NLRP3 variants, rs74163773 and rs10754558, using allele-specific PCR and TaqMan^TM SNP genotyping assay, respectively. Based on our genotype and allelic distribution, rs74163773 variant did not associate with the risk of developing the persistent infection. However, a significant association of heterozygous CG variant of rs10754558 with patient showing clinical symptoms of gastritis, PUD and persistent infection in the over-dominant, co-dominant and recessive models was found. Our findings suggest that persistent H. pylori infection susceptibility was influenced by genetic variant rs10754558 and its heterozygous CG variant can serve as an independent risk factor in the manifestation of chronic gastritis and PUD in the South Indian Tamils.