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. The study included 80 RA patients and 80 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. 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. It is concluded that RA is negatively associated with IL-18 -137CC SNP, and that IL-18 607-SNPs 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.