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To identify genetic factors that predict sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin (RBV) in HIV/hepatitis C virus (HCV) genotype 1 or 4-coinfected patients and that enhance the predictive capacity of IL28B genotype in this population.Prospective cohort study.Five tertiary care centers in Spain.Two hundred and five HIV/HCV genotype 1 or 4-coinfected patients who received a complete course of Peg-IFN/RBV for 48 weeks.All individuals were genotyped for 144 single-nucleotide polymorphisms (SNPs).One hundred and sixty-two (79%) patients bore HCV genotype 1. Overall SVR was achieved by 73 (36%) individuals. SNPs at the following genes were associated with SVR: IL28B, low-density lipoprotein receptor (LDLR), transforming growth factor β (TGF-β), aquaporine 2 (AQP-2), very-low-density lipoprotein receptor, Sp110 nuclear body protein, interferon alpha/beta receptor 1, 2’-5’-oligoadenylate synthase 1 and apolipoprotein B. There was a strong synergy between SNPs at IL28B, TGF-β and AQP-2 genes: the number of patients reaching SVR with all three favorable genotypes versus unfavorable genotypes were 22 (78.6%) versus 1 (7.1%) (P = 2.1 × 10–4). HCV baseline viral load, IL28B, TGF-β, AQP-2 and LDLR haplotypes were independently associated with SVR.A number of genetic factors modify the predictive capacity of IL28B genotype. These can be used to identify HCV genotype 1 or 4-infected patients with a very high or a very low probability to respond to bitherapy with Peg-IFN/RBV. Predictive models based on these factors could be helpful to tailor direct acting antiviral-based therapy.