Serial serum samples and pretreatment and post-treatment liver tissue from patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by reverse-transcription polymerase chain reaction and branched DNA signal amplification assays. At the end of treatment with interferon-alpha (IFN alpha), 4 of 5 patients showing no biochemical response (in alanine aminotransferase activity), 4 of 5 with transient responses, and 1 of 5 showing complete and sustained responses had HCV RNA detectable in serum. The corresponding numbers for liver tissue were 5, 5, and 0 (of 4). However, all 5 complete responders had virological relapses within 6 months. Biochemical response may not reflect virological profile during IFN alpha treatment of HCV.