Previous works have documented the contribution of different IL28B-associated SNPs to spontaneous HCV clearance. This study investigated the effect of different interleukin (IL) 28B genetic variants on interferon (IFN)-based therapy response. We genotyped eight IL28B single-nucleotide polymorphisms (SNPs) in a cohort of 197 hepatitis C virus (HCV)/human immunodeficiency virus type 1 (HIV-1) coinfected patients from our clinic unit who received combined pegylated (peg)-IFN-α and ribavirin (RBV) therapy. This analysis included the two strongest tag predictors for HCV clearance, rs8099917 and rs12979860, and four causal variants (rs4803219, rs28416813, rs8103142, and rs4803217) located in the IL28B promoter, coding, and 3'-untranslated regions. Haplotypes carrying the major alleles at IL28B SNPs were highly associated with sustained virological responses (SVRs) after treatment with peg-IFN-α and RBV [odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.6-4.0, 4.0×10(-5)]. Three causal SNP genotypes (rs28416813, rs8103142, and rs4803217) displayed the highest association with SVRs (OR = 3.7, 95% CI = 2.0-6.7, p = 1.3×10(-5)). All four causal variants were in high linkage disequilibrium, both among themselves (r(2)≥0.94) and with the rs12979860 variant (r(2)≥0.92). In contrast, rs8099917 was in low linkage disequilibrium with the four causal variants (r(2)≤0.45) and with the rs12979860 variant (r(2) = 0.45). These results demonstrate that rs12979860, compared to rs8099917, may be a better predictor of response to the peg-IFN/RBV treatment among HCV/HIV-1 coinfected patients. Moreover, causal IL28B variants are strongly associated with treatment SVRs.