The aim of this study was to investigate the association of interleukin-18 (IL-18) promoter single nucleotide polymorphisms (SNPs) at – 607 and – 137 regions with risk for rheumatoid arthritis (RA) and their association with activity and severity of the disease. Patients and Methods: The study included 80 RA patients and eighty age and sex matched healthy subjects. Forty RA patients and 40 control subjects were randomly chosen to measure their serum IL-18 levels. IL-18 SNPs at – 607 and – 137 regions were analyzed using polymerase chain reaction-sequence specific polymorphism (PCR-SSP) analysis. Results: The frequency of –137CC genotype was significantly lower in RA patients than controls (OR=0.23, 95% CI 0.07-0.72, p= 0.012), while the –607C/A genotypes (CC, CA, AA) showed insignificant differences between patients and controls. No association was found between erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin (HB), DAS 28 and X ray grades and –607C/A and – 137G/C genotypes. Serums levels of IL-18 were not significantly different among individuals with different IL-18 –607 and –137 genotypes. Conclusion: It is concluded that RA is negatively associated with IL-18 –137CC SNP, and that IL-18 607-SNP may not be a risk factors for RA in Egyptian patients with no specific genotype association with disease activity or severity. No specific genotype was associated with higher IL-18 serum levels.