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The contribution of humoral immune responses to spontaneous control of hepatitis C virus (HCV) infection remains unclear. We assessed neutralizing antibody (nAb) responses during acute HCV infection to determine whether infection outcome is associated with the nAb response, specifically, its timing or breadth (neutralization of multiple genotype-matched variants). A representative genotype 1 HCV pseudoparticle (HCVpp) library, consisting of 19 genetically distinct genotype 1 HCVpp that comprise the natural variability of genotype 1 E1E2 sequences, was used to assess anti-genotype 1 nAb responses during acute infection in at-risk persons followed prospectively. Neutralization of individual library HCVpp by the last viremic plasma sample obtained before clearance was compared to either 1-year post-initial viremia or clearance time-matched specimens obtained from subjects developing persistent infection. In persistently infected persons nAb responses were delayed then progressively broadened, whereas in persons who controlled viremia broader responses were detected early and contracted after clearance of viremia. Surprisingly, the breadth of anti-genotype 1 nAb responses was not dependent on subjects' infection genotype. Also, individual library HCVpp neutralization sensitivity was not associated with any known E2 sequence determinants. Interestingly, two single nucleotide polymorphisms in the HLA-DQ locus were associated with nAb breadth. Conclusion: Control of HCV infection is associated with more rapid development of a broad nAb response, independent of the infection viral genotype, providing further evidence for the role of nAb in controlling HCV infection and the potential benefit of generating broad anti-HCV nAb responses by vaccination. (Hepatology 2014;59:2140–2151)