Interleukin-18 (IL-18) is associated with chronic inflammation, autoimmune diseases and various cancers and infectious diseases. An IL-18 genetic A/C polymorphism at coding position 105 (rs549908) has been linked with asthma and rheumatoid arthritis. We tested a hypothesis that the IL-18 genetic polymorphism confers systemic lupus erythematosus (SLE) susceptibility. Study participants were Taiwanese SLE patients and a healthy control group. Our results indicate (1) a significantly higher A allele frequency in SLE patients (P = 0.003; OR = 1.97; 95% CI = 1.26—3.08) and (2) a significantly higher A allele frequency in SLE patients with a central nervous system disorder (P = 0.027; OR = 7.18; 95% CI = 0.95—54.28). Our results suggest that the A/C polymorphism contributes to SLE pathogenesis.