Recently, we have shown that SOCS-1/3 overexpression in hepatic cells abrogates signaling of type I interferons (IFN) which may contribute to the frequently observed IFN resistance of hepatitis C virus (HCV). IFN-λ s (IL-28A/B and IL-29), a novel group of IFNs, also efficiently inhibit HCV replication in vitro with potentially less hematopoietic side effects than IFN-α because of limited receptor expression in hematopoietic cells. To further evaluate the potential of IFN-λ s in chronic viral hepatitis, we examined the influence of SOCS protein expression on IFN-λ signaling. First, we show that hepatic cell lines express the IFN-λ receptor complex consisting of IFN-λ R1(IL-28R1) and IL-10R2. Whereas in mock-transfected HepG2 cells, IL-28A and IL-29 induced STAT1 and STAT3 phosphorylation, overexpression of SOCS-I completely abrogated IL-28A and IL-29-induced STAT1/3 phosphorylation. Similarly, IL-28A and IL-29 induced mRNA expression of the antiviral proteins 2',5'-OAS and MxA was abolished by overexpression of SOCS-1. In conclusion, we assume that despite antiviral properties of IFN-λ s, their efficacy as antiviral agents may have similar limitations as IFN-α due to inhibition by SOCS proteins. © 2005 Elsevier Inc. All rights reserved.