Neutralizing antibodies can prevent hepatitis C virus (HCV) infection, one of the leading causes of cirrhosis and liver cancer. Here, we characterized the immunoglobulin repertoire of memory B-cell antibodies against a linear epitope in the central front layer of the HCV envelope (E2; amino acids 483–499) in patients who were infected in a single-source outbreak. A reverse transcription polymerase chain reaction–based immunoglobulin gene cloning and recombinant expression approach was used to express monoclonal antibodies from HCV E2 peptide–binding immunoglobulin G–positive memory B cells. We identified highly mutated antibodies with a neutralizing effect in vitro against different genotype isolates sharing similar gene features. Our data confirm the importance of V_H1–69 use for neutralizing activity. The data offer a promising basis for vaccine research and the use of anti-E2 antibodies as a means of passive immunization.