Here, we show that the extent of monocyte-induced and IL-12-mediated stimulation of NK cell IFN-γ production is associated with the IL-28B polymorphism in chronic hepatitis C, thereby providing a functional link between λ-IFNs and NK cell activity, which was independent on potentially confounding factors such as viral load or transaminase levels. Here, IFNL3 is linked to chronic hepatitis C virus infection.