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IL28B polymorphisms influence both the rate of spontaneous hepatitis C virus (HCV) clearance and response to interferon α (IFNα)-based therapy. This observation has been reproduced in HIV-co-infected individuals. Controversy exists about the impact of IL28B alleles on HCV load.CoRIS is a nationwide, open cohort of newly diagnosed HIV-1 adults in Spain. In the subset of HCV-co-infected individuals, the relationship between plasma HCV-RNA and IL28B (rs12979860) genotypes was evaluated.A total of 4670 HIV-1-infected patients had been included in CoRIS up to June 2010. All were naive for IFNα. HCV antibodies were reactive in 895 (19%). Of them, 289 specimens were available and tested positive for plasma HCV-RNA, with median values of 959 900 IU/ml. The rs12979860 genotype distribution in HCV viremic patients was CC 45%, CT 42.2% and TT 12.8%. The median plasma HCV-RNA according to IL28B genotypes was: CC 1 385 000, CT 848 939 and TT 251 189 IU/ml (P = 0.006). The percentage of patients with HCV-RNA more than 600 000 IU/ml was: CC 67.7%, CT 56.6% and TT 35.1% (P = 0.001). In multivariate analysis, IL28B CC/CT genotypes, infection with HCV genotypes 1/4 and prior intravenous drug users were independent predictors of HCV-RNA more than 600 000 IU/ml.HIV/HCV-co-infected patients with the C allele (CC/CT) at rs12979860 show significantly higher plasma HCV-RNA load than TT carriers. Notably, plasma HCV-RNA levels associated with poorer response to IFNα-based therapy are significantly more frequent in CC/CT than TT carriers. Hypothetically, patients harboring the rs12979860 allele C could display a lower activity of endogenous IFNα, allowing higher HCV replication while keeping an enhanced susceptibility to exogenous IFNα therapy.