Reports of the role of host interleukin 28B (IL-28B) genetic variants in liver disease severity in patients with chronic hepatitis C (CHC) have obtained conflicting results. The impact of IL-28B in Asian patients with different viral genotypes remains elusive.We try to elucidate the effect of IL-28B genetic variants in a large Asian cohort with different viral genotypes.The association between the IL-28B rs8099917 genotype and liver fibrosis was investigated in 1288 patients with biopsy-proven CHC.Patients with hepatitis C virus genotype 1 (HCV-1) infection comprised 59.4% of the population. The remaining 40.6% (518 patients) did not have HCV-1 infection. Of the 1084 patients with the IL-28 genotype, 85.6% (928 patients) had the TT genotype. Univariate analysis revealed that, compared to patients without advanced liver fibrosis, patients with advanced liver fibrosis (Metavir fibrosis score 3-4) had an older age, a lower platelet count, a higher α-fetoprotein level, a higher alanine aminotransferase level, a higher incidence of diabetes, and a higher frequency of rs8099917 non-TT genotype carriage.Logistic regression analysis revealed that factors significantly associated with advanced liver fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 1.023/1.009-1.037, P = .001), diabetes (OR/CI: 1.736/1.187-2.539, P = .004), α-fetoprotein (OR/CI: 1.007/1.002-1.012, P = .009), platelet count (OR/CI: 0.991/0.988-0.993, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.585/0.400-0.856, P = .006). When patients were classified by viral genotype, factors that had significant independent associations with advanced liver fibrosis in patients with HCV-1 infection included diabetes (OR/CI: 2.379/1.452-3.896, P = .001), α-fetoprotein (OR/CI: 1.023/1.012-1.035, P < .001), platelet count (OR/CI: 0.99/0.987-0.994, P < .001), and carriage of the rs8099917 non-TT genotype (OR/CI: 0.529/0.328-0.854, P = .009). In patients who had advanced liver fibrosis but not HCV-1 infection, factors that had significant independent associations with advanced liver fibrosis included age (OR/CI: 1.039/1.016-1.063, P = .001) and platelet count (OR/CI: 0.99/0.986-0.995, P < .001); additionally, IL-28B genetic variants were not associated with liver disease severity.Unfavorable IL-28B genetic variants were associated with advanced liver disease. The genetic effect is limited to patients with HCV-1 infection.