Previous studies have failed to explain the link between copper accumulation and abnormal caeruloplasmin expression in Wilson's disease. Furthermore, despite the isolation of a candidate gene for Wilson's disease, which predicts a defective copper transport protein, the localization of this putative protein and its relationship to the pathway involved in copper excretion and to caeruloplasmin remain unknown. We now present evidence that caeruloplasmin, the major plasma copper-carrying protein, is present in the liver in Wilson's disease, and thus that reduced circulating levels of the protein result from a post-translational defect in the secretory pathway. We have also identified a novel form of caeruloplasmin, molecular weight 125 kD, which we propose may act as the carrier for excretory copper into bile, since it is normally present in both liver and bile, although largely absent from serum, and undetectable in bile from Wilson's disease patients. The presence of this form of caeruloplasmin in Wilson's disease liver suggests that a related post-translational defect may also be responsible for its absence from bile in Wilson's disease. This study thus provides the first plausible explanation of a link between the defective copper excretion and the reduced plasma caeruloplasmin, which characterize Wilson's disease.