Increased IFN-γ levels have been associated with systemic lupus erythematosus (SLE). However, the relationships among IFN-γ, type I interferons (IFNs) and clinical features have not been extensively studied. Peripheral blood samples from 44 SLE patients and 36 healthy donors (HDs) were collected. Quantitative real-time PCR was used to assess the mRNA expression of IFNG, type II IFN-inducible genes (IRF1, GBP1, CXCL9, CXCL10, and SERPING1, which are used for the type II IFN score), type I IFN-inducible genes (IRF7, MX1, ISG15, and ISG20, which are used for the type I IFN score), TBX21, and EOMES in peripheral blood mononuclear cells. Flow cytometry was used to measure the IFN-γ levels in lymphocytes. The mRNA levels of type II IFN-inducible genes, IFNG, TBX21, and EOMES were significantly higher in SLE patients than those in HDs. Similarly, the percentages of IFN-γ-producing cells in lymphocytes and their subsets in SLE patients were significantly increased. Linear regression indicated that IFNG expression levels and type II IFN scores were positively correlated with anti-double-stranded DNA autoantibody levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores. Compared with patients with low type I IFN scores, patients with high type I IFN scores showed increased type II IFN scores and SLEDAI scores. Type II IFN scores were positively associated with type I IFN scores. The IFN-γ signaling pathway is activated in SLE patients and may be considered an index of disease activity. IFN-γ, together with type I IFNs, promotes the pathogenesis of SLE.