Autoantibodies against C-reactive protein (anti-CRP) were measured and correlated with disease activity measures in serum samples from 25 patients with systemic lupus erythematosus (SLE). Two samples were collected from each patient, one during the control state and the other during disease flare according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The presence of anti-CRP was analysed by enzyme-linked immunosorbent assay (ELISA). The cut-off for positive anti-CRP test was set at the 95th centile of 100 healthy blood donor sera. Serum levels of CRP, anti-DNA antibodies, complement components and blood cell counts were evaluated in the two samples of each patient. Of 50 serum samples, 20 (40%) contained antibodies reactive with monomeric CRP, and all patients with active lupus nephritis were positive for anti-CRP at flare. Anti-CRP data from all patients were positively correlated with SLEDAI scores and anti-DNA antibody levels, whereas significant inverse relationships were noted for complement factors C1q, C3 and C4, and for lymphocyte counts. This study confirms the high prevalence of anti-CRP autoantibodies in SLE and that the antibody levels are correlated with clinical and laboratory disease activity measures. This indicates that anti-CRP antibodies might have biological functions in the pathogenesis of SLE. Further clinical and experimental studies on effects mediated by anti-CRP antibodies are warranted.