Mutations in the core sequence of the HCV genome have been reported to influence treatment response, fibrosis progression, and hepatocarcinogenesis in Asian patients with genotype-1 chronic hepatitis C (CHC). In this issue, Miura et al. report data consistent with a causal relationship between the R70 → Q70 core variant and hepatocellular carcinoma (HCC) risk in CHC genotype-1b patients, by the prospective evaluation of changes in the consensus sequence in the entire open reading frame between treatment failure and HCC development or end of follow-up, and validation of the initial findings in a confirmatory cohort. Furthermore, they observed an association between the IL28B genotype, which is believed to influence the immune response to viral infection, and the direction of time-dependent changes in core residue 70, with unfavorable IL28B genotypes linked to a preferential shift to the 70Q associated with HCC. Although this association needs to be validated in independent cohorts, and IL28B variants did not influence HCC risk, these results suggest that IL28B genotype might not only influence the behavior of the innate immune system in the presence of HCV genotype-1 infection but also shape the resultant viral evolution, with possible consequences on major clinical outcomes, such as HCC development, and treatment response.