IL28B host genetic make-up is known to play a critical role in the outcome of genotype 1 hepatitis C virus (HCV) infection in the context of both primary infection and therapy. However, the role of IL28B in subtype 3a infection remains unclear, and has not yet been assessed in the UK population where subtype 3a is dominant. In this study, we evaluated the role of the IL28B single-nucleotide polymorphism rs8099917 in 201 patients recruited from two well-defined cohorts (from Nottingham and Oxford), treated with the standard-of-care therapy of pegylated interferon and ribavirin for 24 weeks. We showed that the 'favourable' IL28B gene was associated with a rapid virological response to therapy at 4 weeks (P<0.0001), but not with a sustained virological response to therapy. The median viral load at baseline, before therapy, was markedly increased in people with the 'favourable' IL28B genotype [median viral load for the TT allele, 925,961 IU ml(-1) (range 2200-21,116,965 IU ml(-1)), and for the GT or GG allele, 260,284 IU ml(-1) (range 740-7,560,000 IU ml(-1)); P = 0.0010]. Our results suggest that the host genetic response plays an important role in early viral clearance of subtype 3a virus from the blood. However, significant reservoirs of infection must persist, as viral relapse is common, even in those with the favourable host genotype.