Chronic hepatitis C virus (HCV) infection is associated with a variety of clinically important extrahepatic abnormalities. We have assessed the prevalence of cryoglobulinemia and of the clinical syndrome associated with it in patients with chronic HCV infection. We also have evaluated the clinical, serologic, and biochemical response to antiviral treatment with interferon-alpha (IFN-alpha). Eighty-one patients with chronic liver disease associated with HCV infection were included. Cryoglobulins were sought in the serum. All patients were examined carefully for clinical manifestations of cryoglobulinemia (e.g., palpable purpura, Raynaud's syndrome, arthritis, peripheral neuropathy, Sjögren's syndrome, glomerulonephritis). Antiviral treatment with IFN-alpha, at a dose of 3 to 5 million units, 3 times weekly, was given to 20 patients with cryoglobulinemia. Cryoglobulins were detected in 45.7% of patients. Signs and symptoms of the clinical syndrome associated with cryoglobulinemia were present in 12.3% of the entire group of patients (27% of the subgroup with detectable cryoglobulins). Patients with cryoglobulinemia were older (mean age, 56 +/- 15 vs. 44 +/- 16 years; p = 0.002) and had a higher rate of cirrhosis (48.6% vs. 18.2%, rate ratio = 4.26, 95% confidence interval = 2.11 to 8.58, p = 0.00005) compared to patients without cryoglobulinemia. Cryoglobulins disappeared from the serum in 13 (65%) of the 20 patients who were treated for 6 to 12 months with IFN-alpha. This effect was affiliated in most patients with resolution of the clinical findings associated with cryoglobulinemia and return of transaminases to normal levels. Recurrence of cryoglobulinemia was observed in two thirds of the patients who were observed after treatment with IFN-alpha. We conclude that cryoglobulins are present in 45.7% of patients with chronic HCV infection. Symptoms or signs or both associated with the presence of cryoglobulins develop in a high proportion (27%) of these patients. Antiviral treatment with IFN-alpha leads to resolution of both cryoglobulinemia and the symptoms associated with it in most patients who also show a biochemical response to antiviral treatment. Recurrence is frequent after treatment withdrawal.