OBJECTIVE Interferon-gamma (IFNG) is a type II interferon playing diverse roles in innate and adaptive immune systems. Elevated expression of IFNG has been associated with systemic lupus erythematosus (SLE). This study examined the association of IFNG polymorphisms with SLE susceptibility. METHODS Five tag single-nucleotide polymorphisms (SNP) and eight variations in all known regulatory sequences affecting IFNG expression within and around IFNG were genotyped in 1759 unrelated Korean subjects. SLE susceptibility association was assessed by comparing 742 SLE patients and 1017 unaffected controls using multivariate logistic regression analysis with adjustment for age and gender. RESULTS SLE susceptibility association was significant with rs2069705 in the promoter (adjusted OR 2.27, p=0.0024) and marginal with rs3181032 in the promoter (p=0.037), rs2430561 in intron 1 (p=0.022) and rs2069718 in intron 3 (p=0.026) in a recessive genetic model. Five other SNP showed no association and four other variations were not polymorphic. CONCLUSIONS Several SNP in IFNG are associated with SLE susceptibility, and the risk allele of an associated SNP (rs2430561) located in an NF-kappaB binding site has elevated IFNG expression versus the non-risk allele, supporting that elevated IFNG expression is associated with increased SLE susceptibility.