Systemic Lupus Erythematosus (SLE) is an autoimmune disease more prevalent and more severe in American Indian (AI) populations. AI SLE patients are more likely to develop autoantibodies with unknown specificities compared to other races. Previously, we observed that autoantibodies to M2 mitochondrial antigen are over-represented in AI SLE patients. The goal of this study was to explore the frequency of these autoantibodies in a broader sample selection and in comparison to other races. Age, sex and ANA titer matched AI, African American (AA) and European American (EA) serum samples were screened for reactivity to an autoantigen protein array. SLE subjects with reactivity 3 standard deviations above control sera were defined as positive for a given autospecificity. The frequency of positive autospecificities was compared across races. AI SLE subjects have autoantibodies to a broader range of autoantigens compared to AA or EA subjects. Autoantibodies to myositis antigens, TIF1γ, SRP54 and PL-7, occur at a higher frequency in sera from AI SLE subjects compared to AA SLE subjects. The frequency of M2 autoantibodies, specific for primary biliary cirrhosis or LKM1 autoantibodies, specific for autoimmune hepatitis are greater in AI SLE subjects compared to AA or EA subjects. AI SLE subjects, positive for M2, LKM1 and myositis autoantibodies are likely to have elevated liver enzymes or myalgia but only a small number of these subjects have been diagnosed with PBC, AIH or myositis.Systemic lupus erythematosus is more prevalent and more severe in American Indian populations.American Indian systemic lupus erythematosus patients are more likely to develop novel autoantibodies compared to patients from other races.Our research suggests that autoantibodies specific for primary biliary cirrhosis, autoimmune hepatitis, and myositis are more prevalent in American Indian populations.