Background: Interleukin-18 (IL-18) is a pro inflammatory cytokine which plays a key role in the acute and chronic inflammatory phases of Rheumatoid Arthritis (RA). The Single Nucleotide Polymorphisms (SNPs) of IL-18 gene promoter region at positions -137 and -607, are postulated to be associated with RA. To test this, this study aimed to identify the association between these SNPs of the IL-18 gene promoter region of RA in south Indian patients. Materials and Methods:This study was carried on 190 subjects among which 90 were RA patients and 100 were age and sex matched controls. Genomic DNA was extracted by Salting out method. IL 18 gene promotor region SNPs, IL 18 -607 and IL 18 -137 were amplified by using sequence specific primers. The amplified products of different samples were separated by using a 1.5% agarose gel, stained with ethidium bromide and photographed. All statistical analyses were carried out by using SYSTAT 12 software.Results: At position 607, the frequencies of C allele, CC genotype, A allele and AA genotype were found to be significantly higher in patients and controls respectively and there was no significant difference in CA genotype. At position 137, there was no significant difference between the two groups with regard to G and C allelles but there was a significant increase in GG genotype of patients and CC genotype of controls. There was no association between duration of morning stiffness, rheumatoid factor positivity or negativity, age of onset and gender with distribution of genotypes and alleles.