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Type I interferon (IFN) is used for the treatment of chronic hepatitis C virus (HCV) infection. Despite advances in antiviral therapy, a large proportion of patients remain infected following current therapies. Through a genome-wide scan, we found two variants (rs8099917 and rs12979860) in the IL-28B locus that affect the outcome of PEG-IFN and ribavirin combination therapy, consistent with recent studies (P = 6.52×10(-8); odds ratio 2.46 and P = 8.63×10(-8), odds ratio 2.40, respectively). Significant associations were also observed in the case of IFN monotherapy for HCV genotypes 1b and 2a. With rs8099917, HCV genotype 1b patients had a significantly lower frequency of the favourable genotype (86.6 %) compared with healthy controls (91.7 %), and HCV genotype 2a patients had an intermediate frequency (89.9 %). Similar results were found for rs12979860. Fine-mapping analysis revealed that rs8099917 had the strongest association with treatment outcome and 14 others, including four novel single nucleotide polymorphisms, had comparable associations. Haplotype analysis revealed that none of the haplotypes showed stronger association than any single marker. Early non-responders who could not achieve 2 log viral decline during the first 12 weeks of treatment had higher odds ratios for these two variants. The favourable allele of rs8099917 is also associated with initial viral decline at 2 and 4 weeks following the start of therapy. Multivariate analysis of PEG-IFN and ribavirin-treated patients showed that rs8099917 genotype, viral load, fibrosis and age were significant predictors of response to therapy. Common variation at the IL-28B locus is predictive of various IFN-based therapies for HCV independent of regimen or HCV genotype.