In this study, the association between the systemic lupus erythematosus (SLE) susceptibility and the new candidate genes, IFNA1, IFNA2 and IFNA5 genes, major interferon-alpha subtypes, in responses to viral infection was investigated. Allele and genotype frequencies of each marker were compared between 150 SLE patients and 150 healthy control subjects. This study indicated that the A/A genotype of IFNA5 (-2529) and the G/G genotype of IFNA1 (-1823) were associated with the protection of SLE disease in a recessive model [P(c) = 0.03, P = 0.01, odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2-0.8 and P(c) = 0.09, P = 0.03, OR = 0.5, 95% CI = 0.2-0.9, respectively). Multifactor dimensionality reduction analysis showed a marginal interaction between IFNA5 (-2529) and IFNA1 (-1823) gene, with a cross-validation consistency of 10 of 10 and a prediction error of 46% (permutation P-value = 0.05). This is the first report of positive association of IFNA gene in SLE, especially the role of specific subtypes IFNA1 and IFNA5.