The association between the actual status of cryoglobulins (CGs) expression in hepatitis C-related chronic liver disease (C-CLD) and different types of liver pathology, HCV-RNA titers and genotypes was investigated. Sixteen out of 1340 ordinary clinical specimens were CGs-positive (1%), and in 8 of them (50%) the patients blood was HCV-RNA positive. CGs was detected in 63% of C-CLD patients as a whole, but when compared with the histological findings in the liver, it was 88% in F3, and 92% in A3, and thus high percentages were detected in patients with progression of liver fibrosis and patients with strong activity. Serum IgG, IgM, transaminase and gamma-GTP levels were significantly higher in the patients with CGs, and their RA test and C3dCIC levels tended to be higher, but the differences were not significant, and no association was found with the anti-nuclear antibody positive level, or the HCV-RNA titers or genotypes. Based on the above, there was a clear involvement of HCV infection, especially the activity and histological progression of hepatitis in CGs formation in Japan as well, but there were few extrahepatic manifestations, suggesting differences in CGS levels and immune response to CGs from cases in Western countries.