Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with complex genetic inheritance that affecting different organs and systems. STAT4 has been newly identified as a susceptible gene in the development of SLE. According to recent studies, STAT4 has been associated with SLE in various populations. We investigated whether STAT4 single nucleotide polymorphisms (SNPs) were associated with susceptibility and clinical features of SLE in Iranian patients. The study group comprised 280 patients with SLE and 281 sex-, age-, and ethnicity-matched healthy controls of Iranian ancestry. Two SNPs (rs7574865 and rs7601754) were genotyped using the TaqMan MGB Allelic Discrimination method. Our results showed a significant association between rs7574865 T allele (odds ratio (OR) = 1.50, 95 % CI = 1.18-1.92, P = 0.002) and susceptibility to SLE. The rs7574865TT genotype (P = 0.02, OR = 1.94, 95 % CI = 1.74-3.19) and GT genotype (P = 0.008, OR = 1.71, 95 % CI = 1.19-2.45) showed a significant association with the risk of SLE in the Iranian population. We concluded that STAT4 rs7574865 is associated with SLE susceptibility in the Iranian population and this SNP might be a factor in the pathogenesis of SLE. However, further studies are required to investigate the mechanism by which polymorphisms in this gene lead to SLE.