The role of the humoral immune response in the natural course of hepatitis C virus (HCV) infection is widely debated. Most chronically infected patients have immunoglobulin G (IgG) antibodies capable of neutralizing HCV pseudoparticles (HCVpp)in vitro. It is, however, not clear whether these IgG can prevent ade novoHCV infectionin vivoand contribute to the control of viremia in infected individuals. We addressed this question with homologousin vivoprotection studies in human liver–urokinase-type plasminogen activator (uPA)+/+ severe combined immune deficient (SCID) mice. Chimeric mice were loaded with chronic phase polyclonal IgG and challenged 3 days later with a 100% infectious dose of the acute phase H77C virus, both originating from patient H. Passive immunization induced sterilizing immunity in five of eight challenged animals. In the three nonprotected animals, the HCV infection was attenuated, as evidenced by altered viral kinetics in comparison with five control IgG-treated animals. Plasma samples obtained from the mice at viral challenge neutralized H77C-HCVpp at dilutions as high as 1/400. Infection was completely prevented when, before administration to naïve chimeric mice, the inoculum was pre-incubatedin vitroat an IgG concentration normally observed in humans.Conclusion:Polyclonal IgG from a patient with a long-standing HCV infection not only displays neutralizing activityin vitrousing the HCVpp system, but also conveys sterilizing immunity toward the ancestral HCV strainin vivo, using the human liver–chimeric mouse model. Both experimental systems will be useful tools to identify neutralizing antibodies for future clinical use.