A subgroup of patients suffering from primary Sjögren's syndrome (pSS) display unexplained low levels of complement components C3 and/or C4 which is associated with increased risk of non-Hodgkin's lymphoma. C4b-binding protein (C4BP) is a major fluid-phase complement inhibitor which can influence C4 and C3 levels. Therefore we analysed C4BP levels in the sera of patients with pSS to better understand the disturbances in complement in pSS. Associations with other disease markers were also investigated to define a possible role of C4BP as marker of high-risk disease course. Plasma levels of C4BP were analysed in pSS patients (n=86) and in controls (n=68) by ELISA. C4BP levels from 49 patients were correlated to disease activity markers and autoantibody profiles. We found that total C4BP plasma levels were significantly higher in pSS patients compared with controls. C4BP levels correlated to the acute phase response, to levels of C4 and C3 as well as to the CD4+/CD8+ T-cell ratio. C4BP levels were inversely related to IgG levels, extent of autoantibody production and global disease activity. C3dg levels, a marker of complement activation, displayed a negative correlation to C4 levels but interestingly not to C4BP levels. In conclusion, C4BP levels are increased in patients suffering from pSS proportional to their acute phase response. However, in the most active cases, with the most widespread autoantibody production, C4BP levels were decreased in parallel with levels of C3 and C4 and CD4+ T cells, suggesting that disturbed complement regulation may contribute to pathogenicity in pSS.