The quantitation of hepatitis C virus (HCV) viremia can be helpful in the diagnosis, therapy, and monitoring of patients with chronic hepatitis C. A sensitive and quantitative fluorescence enzyme immunoassay (FEIA) has recently been developed for assaying HCV core protein in serum. To assess the utility of measurements of serum HCV core protein during the course of treatment of chronic hepatitis C, we studied 27 patients who were treated with a single schedule of interferon alfa (IFN-alpha) (9 million units per dose for 24 weeks; total dose, 720 million units). Eleven of the 27 patients responded with clearance of HCV RNA and fall of aminotransferase to normal; 16 patients did not respond to treatment. Before therapy, HCV core antigen was detectable in 25 of the 27 patients (93%). The initial serum concentration of HCV core protein was significantly (P < .01) higher in the nonresponders versus the responders. Two weeks after initiating IFN-alpha therapy, HCV core protein was not detectable in any of the 11 responders, but was detected in 8 of 16 nonresponders (P < .01). All responders, but none of the nonresponders, remained negative for core protein after IFN-alpha therapy. The measurement of HCV core protein by FEIA may be useful for predicting the response to IFN-alpha and for monitoring its therapeutic efficacy.