Background IL-21R polymorphisms have been identified as potential predictors of virological outcomes in Western chronic hepatitis C (CHC) patients receiving interferon-based treatment. We aimed to examine the associations of IL-21R genotypes and serum IL-21 levels with virological responses to interferon-based treatment in Asian CHC patients. Methods Genomic and clinical data were collected from 178 consecutive Taiwanese HCV genotype 1 patients who received interferon-based therapy and 72 non-HCV healthy subjects. Among them, serum IL-21 levels, IL-21R and IL-28B genotypes were determined in 124 CHC patients and healthy controls. Results Among patients with IL28B rs8099917 non-TT genotypes, patients with IL-21R rs3093390 CC genotype had a higher sustained virological response rate than those with non-CC genotypes (CC versus non-CC 14/24 versus 0/4; P=0.031). Compared with non-HCV controls, CHC patients had higher serum IL-21 levels (mean ±sd HCV versus non-HCV 377.8 ±780.9 versus 70.5 ±33.2 pg/ml; P=0.001). Patients with sustained virological response had higher pretreatment serum IL-21 levels than those without (adjusted OR 0.23, 95% CI 0.07, 0.80; P=0.021). Conclusions CHC patients have higher serum IL-21 levels than healthy adults. Higher pretreatment serum IL-21 levels and IL-21R polymorphisms may serve as potential factors predictive of treatment outcomes in CHC patients with interferon-based therapy.