The authors studied the interrelationship of antibody to hepatitis C virus core protein (anti-HCV core), antibody to C100-3 antigen (anti-C100-3) and serum hepatitis C virus RNA positivity in chronic liver disease patients. Anti-HCVcore was detected with high titers in 95% (69/73) of chronic non-A, non-B hepatitis patients, while anti-C100-3 was found in 60% (44/73). A close relationship was observed between detection of anti-HCVcore and viremia. Anti-HCVcore was also detected with low titers in 24% (10/41) of hepatitis B virus carriers negative for anti-C100-3. Hepatitis C virus RNA was found in 3 of the 10 anti-HCVcore-positive carriers. A significant correlation was observed between the occurrence of high titers of anti-HCVcore and serum hepatitis C virus RNA positivity. In chronic hepatitis C patients treated with interferon-alpha, a sustained reduction of anti-HCVcore was more closely associated with sustained virus clearance than that of anti-C100-3. These results indicate that anti-HCVcore may serve as a reliable marker of hepatitis C virus infection.