Hypertension, vascular inflammation and renal inflammation are characteristic of systemic lupus erythematosus (SLE), a multisystem autoimmune disease that is complex and poorly understood. Oxidation products of arachidonic and other fatty acids, termed isolevuglandins (isoLG) lead to formation of post-translational protein modifications that are immunogenic. We demonstrate isoLG enrichment in dendritic cells (DCs), B cells, and plasma cells from juvenile female B6.SLE123 mice. In adult B6.SLE123 and NZBWF1 mice, isoLG adducts are enriched in plasma cells and splenic DCs compared to C57Bl/6 and NZW mice respectively. Treatment with the isoLG-scavenger 2-hydroxybenzylamine (2-HOBA) reduced blood pressure, improved renal function, and attenuated renal injury. Moreover, 2-HOBA reduced bone marrow plasma cells, total IgG levels, and anti-dsDNA antibody titers. We also demonstrate that mice with SLE generate specific IgG antibodies against isoLG adducted protein, confirming the immunogenicity of isoLG adducts. Finally, we found that isoLG adducted peptides are markedly enriched in monocytes from patients with SLE which was accompanied by an increase in superoxide production. These findings support a role of isoLG adducts in the genesis and maintenance of systemic autoimmunity and its associated hypertension in SLE. Scavenging of isoLGs promises to be a novel therapy for this disease.