A prospective study was undertaken to evaluate the prevalence, incidence, clinical spectrum and prognostic value of mixed cryoglobulinaemia in HCV infection. Four-hundred and thirty-two consecutive patients with chronic liver disease, 303 HCV-related, 81 HBV-related, 14 nonB-nonC related, and 34 of non-viral aetiology were studied. Cryoglobulinaemia was detected in 139 (46%) of the HCV-related chronic hepatitis patients, in 4 (5%) of the HBV-related and in none of the chronic hepatitis patients of any other aetiology. Cryoglobulinaemia was associated with liver cirrhosis, the duration of liver disease and predominantly with the female sex. HCV and anti-HCV antibodies were present in all the cryoprecipitates. All the HCV genotypes were associated with cryoglobulinaemia. In a high percentage of patients, the amount of cryoglobulinaemic was low and about half of the cryoglobulinaemic patients showed a clinical syndrome. The incidence per year of cryoglobulinaemia (6%) and of related signs was low. A higher incidence of malignant lymphoproliferative diseases was observed in type II cryoglobulinaemia. The presence of a cryoglobulinaemia-related clinical syndrome plays a role in the prognosis of patients with chronic hepatitis C.