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The World Health Organization (WHO) has estimated that about 3% of the world’s population is currently infected with Hepatitis C Virus (HCV). Although spontaneous clearance of HCV infections occurs in 10-20% of patients, nearly 185 million people are still chronically infected by HCV, which is one of the leading risk factors for developing liver cirrhosis and/or liver cancers. In the HIV-1 infected population, chronic HCV infection has become one of the leading causes of non-AIDS specific morbidity and mortality. In the United States about 25% of HIV-1 positive individuals have co-infections with HCV. It has been observed that HIV-1 infection reduces the rate of spontaneous clearance and exacerbates the clinical course of HCV infection in HIV/HCV co-infected individuals, but the mechanisms driving this remain unknown. One of the major hurdles of studying the mechanisms of HCV infection over the last two decades has been the inability to grow and study this virus in a laboratory setting, as well as, the inability to develop reliable animal models. The development of the HCV pseudotyped viral particles (HCVpp) system was ground-breaking and became one of the most important in vitro study tools to test the neutralizing antibodies against virus entry and vaccine studies. Therefore, we used HCVpp to evaluate the role of neutralizing antibodies in an HIV-infected subject who spontaneously cleared HCV, but subsequently was re-infected with a different genotype of HCV. In this study, we examined the role of HCV specific neutralizing antibodies in HCV clearance and chronicity in a HIV/HCV co-infected subject who was enrolled in Pittsburgh portion of the Multicenter AIDS Cohort Study (MACS). The subject’s records showed a 10year history of HIV infection and treatment with antiretroviral drugs for 2 years prior to HCV infection. According to our previous studies, this person was consecutively infected with two different genotypes of HCV. By sequence analysis, the initial infecting HCV genotype was 3a and the subsequent infecting genotype, 1.5 years later, was HCV 1a. Sequence analysis of HCV with longitudinal samples from this individual shows that the initial infecting HCV 3a was cleared spontaneously after one and half year infection, but after the subsequent infecting HCV 1a established its chronic infection in this individual. We hypothesized that neutralizing antibodies played an important role in controlling and clearing the HCV 3a infection, but had minimal impact on the HCV 1a infection. Using HCVpp containing autologous envelope proteins of HCV subtype 3a or 1a, we measured the neutralization activity of antibodies present in the subject’s serum. We found that after pre-incubating genotype 3a specific HCVpp with the subject’s serum collected 6 months after HCV 3a infection, there was a tendency of reduction in the genotype 3a specific HCVpp infectivity. However, we observed no reduction in infectivity of genotype 1a specific HCVpp, which were pre-incubated with the subject’s serum collected after HCV 1a infection. Therefore, our results suggest that the development and presence of neutralizing antibodies may be important for the spontaneous clearance of HCV 3a in HIV co-infected individuals. This study contributes to our understanding of immune control of HCV, which may lead to the development of preventive vaccine against HCV and have a great Public Health impact in preventing HCV infection.