Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex pathogenesis involving multiple genetic and environmental contributions. Single-nucleotide polymorphisms (SNPs) in cytokine genes are associated with higher or lower cytokine activity, which can alter the susceptibility to certain diseases or their clinical outcomes. We investigated SNPs of the IL-1 family in Iranian SLE patients and normal individuals. We obtained blood samples from 207 SLE patients and 213 healthy controls. Cytokine genotyping was performed by polymerase chain reaction with sequence-specific primers. The following SNPs were assessed: IL-1A rs1800587, IL-1B rs16944 and rs1143634, IL-1R1 rs2234650 and IL-1RN rs315952. The frequency of the IL-1RN rs315952 CT genotype was significantly lower among patients with SLE compared with healthy controls (OR = 0.63, 95 % CI = 0.42-0.95; P < 0.05 relative to reference genotype and OR = 0.62, CI = 0.42-0.93; P < 0.05 relative to homozygous genotypes). For all other studied alleles and genotypes, there were no significant differences concerning genotype frequencies between patients and controls. A significant increase in IL-1RN rs315952 T allele frequency was noted in patients with a hematologic manifestation (OR = 1.75; 95 % CI = 1.07-2.84; P = 0.033). Polymorphism in IL-1RN rs315952 was significantly associated with SLE in Iranian patients, rs315952CT genotype being a protective factor. We found that IL-1RN rs315952 T allele frequency was significantly higher in patients with hematologic manifestations. Variation at this locus may affect IL-1 receptor antagonist activity, supporting the hypothesis that altered or imbalanced IL1 production may affect the risk of developing SLE.