OBJECTIVE To evaluate the prevalence and correlates of anti-pentraxin 3 (PTX3) antibodies in systemic lupus erythematosus (SLE). METHODS Serum samples from 130 patients with SLE, 130 age- and sex-matched healthy subjects and 130 patients with other autoimmune rheumatic diseases (oARD) were analysed by home-made ELISAs using as substrate human recombinant PTX3 and two peptides, PTX3_1 and PTX3_2, obtained from the complete protein, identified as potential antigenic sites using the Lasergene DNA program (DNA Star). Inhibition tests were performed to evaluate potential interferences between bovine serum albumin or C-reactive protein and anti-PTX3 or anti-PTX3 peptides, and between antigens and antibodies. Statistical analysis was performed using receiving operating characteristics curves, the Fisher exact test, two-tailed t test and Pearson correlations. RESULTS Patients with SLE had higher levels and prevalence of anti-PTX3, anti-PTX3_1 and anti-PTX3_2 antibodies than patients with oARD or healthy controls (p<0.001 for all). No differences were observed between patients with oARD and healthy controls. A correlation was found between anti-PTX3 and anti-PTX3_2 antibodies (r=0.615, p<0.001). No association was observed between these antibodies and disease activity. Univariate and multivariate analyses showed that anti-PTX3 and anti-PTX3_2 antibody levels and prevalence were higher in patients without glomerulonephritis and in patients positive for antiphospholipid antibody. All inhibition tests were negative apart from PTX3 against anti-PTX3 antibody or, to a lesser extent, against anti-PTX3_2 antibody, and PTX3_2 against anti-PTX3_2 antibody, all in a dose-dependent manner. CONCLUSIONS Anti-PTX3 antibodies are significantly prevalent in patients with SLE where they might provide protection from renal involvement. The antigenic properties of PTX3_2 peptide are similar to those of PTX3, suggesting its potential use in further analyses.