Type I interferons are associated with lupus. Genes that are regulated by IFN-α are upregulated in pediatric lupus patients. Gene deletion of the IFN-α/β receptor in experimental lupus-like NZB mice results in reduced disease activity. Conversely, IFN-β is a well-established treatment in multiple sclerosis, another autoimmune disease. For determining whether IFN-β treatment is harmful or beneficial in lupus, MRL-Fas lpr mice were injected with this type I IFN. Treatment was initiated in MRL-Fas lpr mice with mild and advanced disease. IFN-β was highly effective in prolonging survival and ameliorating the clinical (renal function, proteinuria, splenomegaly, and skin lesions), serologic (autoantibodies and cytokines), and histologic parameters of the lupus-like disease in mice that had mild and advanced disease. Several underlying mechanisms of IFN-β therapy involving cellular (decreased T cell proliferation and infiltration of leukocytes into the kidney) and humoral (decrease in IgG3 isotypes) immune responses and a reduction in nephrogenic cytokines were identified. In conclusion, IFN-β treatment of lupus nephritis in MRL-Fas lpr mice is remarkably beneficial and suggests that IFN-β may be an appealing therapeutic candidate for subtypes of human lupus.