To investigate the role of interferon regulatory factor‐1 (IRF‐1) in the development of lupus nephritis, IRF‐1^–/– genotype mice were bred onto the MRL/lpJfas^lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF‐1^–/– mice produced significantly lower levels of nitric oxide and IL‐12 but not TNF‐α when stimulated with LPS + IFN‐γ. IRF‐1^–/– mice showed less aggravated dermatitis compared to the wild‐type mice. Anti‐double‐stranded DNA production and proteinuria were significantly decreased in IRF‐1^–/– mice compared to IRF‐1^+/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF‐1^–/– mice at 26 wk of age compared to the IRF‐1^+/+ mice. Splenic CD4^–CD8^–CD44⁺ T cells were decreased while CD4⁺CD25⁺ T cells were increased in the IRF‐1^–/– mice when compared to IRF‐1^+/+ mice. Survival rates (ED₅₀) were 22 wk for IRF‐1^+/+ mice and 45 wk for IRF‐1^–/– mice. These findings suggest an important role of IRF‐1 in mediating renal disease in MRL/lpr mice.