Genome-wide association studies (GWAS) identified a single nucleotide polymorphism (SNP) rs12979860 located upstream of the IFNL3 (IL28B) gene as a genetic variant strongly predictive of spontaneous and treatment-induced HCV clearance. Further genetic and genomic studies showed that rs12979860 is located in the intronic region of a novel gene, IFNL4, and is in linkage disequilibrium (LD) with an IFNL4 exonic frame-shift polymorphism rs368234815-TT/ΔG. The rs368234815-ΔG allele, which creates an open reading frame for a novel human interferon, IFN-λ4, is strongly associated with decreased HCV clearance. The rs368234815-ΔG allele is a major allele in individuals of African ancestry (70%), while it is less common in Europeans (30%) and Asians (0-5%). Primary human hepatocytes are the only currently known cell type where IFN-λ4 expression can be induced by stimulation with Poly(I:C) or by infection with HCV. In contrast with other interferons, IFN-λ4 is poorly secreted. Using live quantitative fluorescence microscopy we show that a significant proportion of IFN-λ4 transiently overexpressed in HepG2 cells remains intracellularly retained, consistent with its poor secretion. We show that intracellular retention of IFN-λ4 is associated with increased cell death. Treatment with the pan-caspase inhibitor Z-VAD but not with the caspase-1 inhibitor Y-VAD decreased the IFN-λ4-induced cell death. We also observed increased caspase 3 activation in both primary human hepatocytes and HepG2 cells, transiently overexpressing IFN-λ4, suggesting apoptosis as a mechanism of cell death. In conclusion, we propose a novel mechanism associated with pathogenic effect of IFN-λ4 in human hepatic cells through induction of apoptotic cell death. Induction of IFN-λ4 in HCV-infected hepatocytes leading to cell death and tissue repair in the liver, may result in hepatic fibrosis and cirrhosis, which are relevant factors affecting clearance of HCV and, possibly progression to hepatocellular carcinoma.