Long-term serial serum samples containing hepatitis C virus (HCV) from the US and Japan were molecularly clocked to determine the time-origin of the HCV epidemic. Based on the molecular clock that held significantly, it is estimated that HCV genotype 1 first appeared in the US around 1910 whereas in Japan HCV surfaced before 1882. By regression analyses and coalescent theory, widespread dissemination of HCV in the US population occurred during the 1960s, approximately 30 years later than in Japan. Currently, the prevalence of hepatocellular carcinoma (HCC) is strikingly higher in Japan than in the US. If HCC is a function of increased HCV exposure time, the molecular clock predicts that the burden of HCC in the US will accelerate in the next two to three decades.