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BACKGROUND AND AIMS: Neutralising antibodies (NAb) play a key role in clearance of hepatitis C virus (HCV). NAbs have been isolated and mapped to several domains on the HCV Envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering vaccine efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitope-specific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. METHODS: Using samples from 168 subjects with primary HCV infection, the antibody responses targeted two immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains. RESULTS: No epitopes were uniquely targeted by clearers versus those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards epitopes AR3, AR4 and domain D, and did not target non-neutralising domains. CONCLUSIONS: This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains.