To elucidate precisely the prevalence and significance of cryoglobulinemia in hepatitis C, we examined the prevalence of serum cryoglobulin (CG) among 232 consecutive hepatitis C virus carriers (23 asymptomatic carriers, 164 with chronic hepatitis, 45 with cirrhosis), 30 consecutive hepatitis B virus carriers and 100 age- and sex-matched healthy volunteers. We used a gel-diffusion procedure that detects CG with greater sensitivity and specificity than the conventional precipitation method. Among the 232 patients, 166 were tested for the presence or absence of CG by the precipitation method also, which showed 60 (36.1%) patients to be positive for CG. On the other hand, 164 of the 232 patients (70.7%) were positive for CG using the diffusion method. 5 (16.7%) of the 30 HBV carriers and 2 (2%) of the healthy volunteers also were positive for CG using the gel-diffusion procedure. CG was detected more frequently among the patients with chronic hepatitis or cirrhosis than the asymptomatic carriers. In spite of the high prevalence of CG positivity, only one patient had symptoms related to cryoglobulinemia. Positivity for CG was not related to viral serogroup, viral load or the presence of antinuclear antibody, but it was related closely to CH50: 58 of 63 (92.1%) patients with lower levels of CH50 were positive for serum CG. In conclusion, cryoglobulinemia is a very common feature of chronic hepatitis C.