Abstract An assessment of the frequency of serum autoantibodies against modified C-reactive protein (mCRP) in systemic rheumatic diseases and the association of these autoantibodies with clinical and laboratory findings in patients with systemic lupus erythematosus (SLE). Serum levels of autoantibodies against mCRP were measured by an enzyme-linked immunosorbent assay in 125 patients with SLE and in 213 patients with other systemic rheumatic diseases. The frequency of patients with high antimodified CRP antibody levels was 32% in SLE, 22% in systemic sclerosis (SSc), 19% in polymyositis/dermatomyositis (PM/DM), 43% in primary Sjogren's syndrome (pSS), 29% in rheumatoid arthritis (RA), 33% in mixed connective tissue disease (MCTD), and 43% in overlap syndrome. Serum levels of anti-mCRP antibody were significantly lower in SLE patients with persistent proteinuria (P < 0.001), cellular casts (P < 0.01), and hypoalbuminemia (P < 0.05). Serum anti-mCRP antibody levels in SLE showed a direct correlation with serum IgG levels (P < 0.001), serum anti-SS-A antibody levels (P < 0.01), serum anti-SS-B antibody levels (P < 0.01), and serum anti-U1-RNP antibody levels (P < 0.05). Inhibition experiments revealed that nonnative epitopes on the CRP molecule, termed mCRP, were the main target of the anti-mCRP antibodies detected. Autoantibodies against mCRP were frequently found in sera from patients with systemic rheumatic diseases, and may have a role in the immunopathogenesis of systemic rheumatic diseases, which are characterized by persistent inflammation.