Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV‐specific immune responses, and that all vaccinees exposed to heterologous chimpanzee‐adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P = 0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA‐4 (1) and PD‐1 levels in liver correlated with clearance or chronicity. Conclusion: Despite early control of virus load, a virus‐associated tolerogenic‐like state can develop in certain individuals independent of vaccination history. (HEPATOLOGY 2007;45:602–613.)