Hepatitis C virus (HCV) is a major cause of liver disease worldwide. Understanding the mechanisms responsible for the establishment of chronic HCV infection is critical to the development of efficient therapeutics and vaccines. The mechanism of intra-host HCV evolution assumed by most models is based on immune escape via random mutations. However, continuous immune escape does not explain our observation of a consistent increase in negative selection during chronic infection, which suggests extensive intra-host HCV adaptation. Using a model of cross-immunoreactivity, we show that the level of HCV intra-host adaptation correlates with the rate of cross-immunoreactivity among HCV quasispecies. We present a mathematical model describing the immunological interaction among quasispecies that involves, in addition to neutralization, a non-neutralizing cross-immunoreactivity. The model describes how HCV variants escape immune responses and persist, owing to their capability to stimulate non-neutralizing immune responses developed earlier against preceding variants without eliciting specific responses against the variant itself.