We have recently described the novel autoantigen plasminogen activator inhibitor (PAI-1) in systemic lupus erythematosus (SLE). The aim of this study was to determine the prevalence and clinical significance of anti-PAI-1 autoantibodies in patients with SLE. Autoantibodies to recombinant PAI-1 were measured in retrospective sera of 48 lupus patients by immunoassay in order to assess their clinical significance. This showed that 71% of sera from 48 lupus patients had significantly elevated anti-PAI-1 autoantibodies as compared with normal control subjects (P <0.0001). There was a weak but significant (P <0.043) correlation with anti-dsDNA autoantibodies. In longitudinal studies, autoantibodies against PAI-1 correlated with clinical parameters measured by the BILAG disease activity index including global clinical score. Our study demonstrates the high frequency of novel autoantibodies to PAI-1 in patients with lupus. The serial clinical correlations with anti-PAI-1 autoantibodies also support the hypothesis that these autoantibodies may play a pathogenic role in lupus.