In a companion study, we showed a dichotomy between the expansion of central memory (CCR7⁺) hepatitis C virus (HCV)‐specific CTL and the incomplete memory effector differentiation in patients with acute HCV infection. Indeed, effector cells were unable to perform immediate functions, despite expressing the tissue‐homing phenotype of effector memory cells (CCR7^–; semi‐effectors). However, since they promptly differentiated into full‐effectors upon IL‐2 contact, we suggested that the inhibitory effect by environmental (possibly viral) factors on IL‐2 production may have a pivotal role in generating the large population of semi‐effector CCR7^–/IFN‐γ^– CTL. In accord with this view, we report here strong evidence in support of circulating HCVcore protein (HCVcore) playing a central role in inhibiting effector CTL differentiation, but not memory CTL expansion. The regulatory HCVcore effect is related to inhibition of the signal transduction pathway instrumental for IL‐2 production, supporting the evidence that IL‐2 was capable both of pushing semi‐effector CTL to complete their effector cell program and of restoring the HCVcore‐dependent inhibitory effect. Therefore, the strength of CTL activation is dependent on the balance between the threshold of stimulatory signals and the viral interference capacities provided during priming.