Several studies by microarray analysis and real-time polymerase chain reaction (RT-PCR) reveal that type I interferon-inducible genes (IFIGs) are implicated in systemic lupus erythematosus (SLE). To find a potential clinical biomarker capable of monitoring lupus disease activity clinically, quantitative RT-PCR was used to identify transcript expression levels of 13 type I IFIGs in peripheral blood cells in 144 patients with SLE, 27 non-SLE patients and 60 healthy controls and then analyse connections between gene expression and disease activity. The expression levels of five type I IFIGs (LY6E, OAS3, IFIT4, OAS1 and OAS2) were significantly higher in the SLE group than in the healthy and non-SLE controls. LY6E gene that had highest expression was chosen to analyse the association of expression level with clinical features. Compared to low LY6E expression group, SLE patients with high LY6E expression had higher SLEDAI-2K score, increased 24 h urine protein and lower blood C3 complement. Active SLE patients had more elevated LY6E expression than stable patients. And LY6E expression levels in patients with SLE were strongly correlated with their SLEDAI-2K scores. Our results indicate that increased expression of LY6E gene in peripheral blood cells in patients with SLE is correlated with lupus activity and may be a useful, noninvasive biomarker for assessing SLE disease activity.