The pathogenesis of hepatitis C virus (HCV) infection is likely to be associated with viral replication in vivo, but little is known concerning the dynamics of HCV turnover. We performed serial measurements of serum HCV-RNA levels following orthotopic liver transplantation (OLT) in nine patients with HCV-positive cirrhosis. Serum HCV-RNA levels were determined by quantitative polymerase chain reaction before, immediately after, and for up to 1 month after OLT. There was a rapid decline in HCV-RNA levels from 3.1 ± 1.3 × 105 copies/ mL (mean ± SEM) preoperatively to 0.15 ± 0.6 × 105 copies/mL on the first and 0.16 ± 0.6 × 105 copies/mL on the second postoperative day (mean viral half-life, 4.0 ± 0.5 h). Thereafter, HCV-RNA levels increased in all but one patient, and by postoperative day 8 reached 3.6 ± 1.3 × 105 copies/mL, exceeding the preoperative levels irrespective of the use or not of rescue immunosuppressive therapy including steroid bolus administration. In most patients, serum virions continued to increase averaging 11.6 ± 2.8 × 105 copies/mL on the 30th postoperative day. These findings indicate that the half- life of HCV is quite short, and that extrahepatic viral replication contributes little to the total virus pool in serum. Furthermore, the marked HCV replication beginning as early as the third postoperative day strongly suggests that the liver graft is rapidly reinfected by HCV after OLT.