With the introduction of interferon therapy for liver disease due to chronic viral hepatitis, it has become important to test individuals thought to have hepatitis C virus disease for the presence of the virus. Moreover, the current goal of therapy for hepatitis C virus-positive liver disease is to render the individual patient HCV-RNA negative. Recently, it has been reported that as many as one-third of the patients with hepatitis C virus liver disease test positive for the presence of mixed cryoglobulins. Few of these cryoglobulin-positive patients have overt disease manifestations of cryoglobulinemia, such as nephropathy, peripheral neuropathy and vasculitis. Because the cryoglobulins in patients with hepatitis C virus-positive disease are directed at hepatitis C virus epitopes, the precipitation of cryoglobulins from serum samples also effectively removes virus. When the viral carriage rate is low in terms of the number of genomes/unit serum, as occurs in cases that are partially treated, the serum can test negative for hepatitis C virus even by polymerase chain reaction, despite the presence of persistent viremia, if precautions preventing the precipitation of cryoglobulins prior to the removal of the sample for polymerase chain reaction testing are taken. From a group of 75 patients with hepatitis C virus-positive hepatitis seen at our institution in the last year (all HCV-RNA positive), 35% were found to test positive for the presence of cryoglobulins. Importantly, in all cases, the cryoglobulins collected tested strongly positive for HCV-RNA.(ABSTRACT TRUNCATED AT 250 WORDS)