We evaluated the influence of cryoglobulinemic syndrome (CS) on the outcome of chronic hepatitis C virus (HCV) infection in a 15-year prospective study. We assessed a cohort of 950 chronically HCV-infected patients, collected from the beginning of 1990 to the end of 2010. All patients had received a liver histologic diagnosis. Mixed cryoglobulinemia (MC) was determined in 246 patients (25.8%), of whom 184 also had CS. They were assessed every 3 months for 15 years, at least; 141 patients with CS and 601 without MC completed the study. No spontaneous clearance of cryoglobulins was noted. Type II to type III spontaneous switching was ascertained in 1.6% (0.08%/yr) patients. The estimated progression rate of liver fibrosis was lower in CS(+) than in MC(−) patients (p