BACKGROUND: The hepatitis C virus (HCV) causes significant morbidity and mortality worldwide, and is highly prevalent among injecting drug users (IDUs). Whether initial HCV infection and clearance provides protection from reinfection has not been established, but is an important question for vaccine development. OBJECTIVE: To elucidate an unusual history of HCV infection and clearance in an IDU. STUDY DESIGN: The subject was interviewed and gave blood samples at approximately three-month intervals; all samples were tested for anti-HCV and HCV RNA, genotyped if RNA detected, and checked for mixed genotypes; phylogenetic analysis performed on the subject’s and injecting partners' core HCV sequences. RESULTS: We observed consecutive infections with HCV genotypes 3a, 1a and 6l, and intervening clearances, in a young IDU over 449 days. Genotypes 1a and 6l were probably acquired from the subject’s injecting partners, who had genetically related infections. CONCLUSION: This case illustrates (1) the ease with which IDUs can acquire HCV, (2) that prior HCV infection does not protect against reinfection with heterologous strains, and (3) that IDUs can clear consecutive HCV infections. Our subject’s history of HCV infection and clearance offers hope for vaccine development, yet demonstrates that HCV vaccines must have cross-genotypic effectiveness.