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Objectives Systemic lupus erythematosus (SLE) is characterised by an activated interferon (IFN) system as well as by the formation of multiple autoantibodies (autoAbs). Interestingly, even autoAbs against IFN type I have been described to occur in SLE and are known to increase susceptibility to viral infections. Epstein-Barr Virus (EBV) causes chronic infection with strong evidence for an association with autoimmune diseases, and is known for increased reactivation rates in SLE. We hypothesize that EBV reactivation is linked to autoAbs against type I IFN.Methods 378 patient plasma samples collected in the context of the Swiss SLE Cohort study (SSCS) were analysed for autoAbs against type I IFN subtypes alpha2, beta and omega using a bead-based Luminex assay, and their neutralisation activity as well as the level of type I-III IFN activation in a cell-based assay. EBV reactivation was assessed in anti-IFN autoAbs positive samples and matched controls using VCA-IgM antibodies ELISA and viral plasma DNA PCR.Results IFN activation levels were high in 105 (28%) of the SLE samples and correlated closely with disease activity as measured by SELENA-SLEDAI and physician’s global assessment (PGA) score. SLE patients showed a high rate of autoAbs against type I IFNs (anti-alpha2 n=40 (11%), anti-beta n=27 (7%), anti-omega n=31 (8%)). Only a minority of autoAbs was neutralising in the cell-based assay used. Subtypes of the type I IFN autoAbs related differentially to clinical manifestation.EBV reactivation was rare (n=7, 4%). While the majority of samples with EBV reactivation had anti-IFN autoAbs (5 out of 7) this did not reach statistical significance. Anti-IFN beta was the most prevalent autoAb (n=4).Conclusions We confirm high anti-type I IFN autoAbs rates in SLE patients and can observe subtype specific relations to disease activity. EBV reactivation was more common in samples with anti-IFN autoAbs, predominantly anti-IFN beta. However, the incidence of EBV reactivation was low resulting in insufficient statistical power. Future studies should be performed on larger cohorts. Furthermore, longitudinal studies will be important to explore the stability of anti-IFN autoAbs and the temporal relation of EBV reactivation, IFN activation and development of anti-IFN autoAbs.