AIM: To study the amino acid substitutions in the carboxy (C)-terminal part of E2 protein and in the interferon (IFN) sensitivity determining region (ISDR)and their correlation with response to IFN and viral load in 85 hepatitis C virus (HCV)-1b-infected patients treated with IFN.METHODS: The C-terminal part of E2 (codons 617-711)including PKR/eIF2α phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-1b-infected patients treated by IFN monotherapy.RESULTS: The amino acid substitutions in PePHD detected only in 4 of 85 patients were not correlated either with response to IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C-terminal part of E2was significantly correlated with both small viral load (33.9% vs 13.8%, P=0.0394) and sustained response to IFN (25.0% vs 6.9%,P=0.0429). Four or more substitutions in ISDR were significantly correlated with both small viral load (78.6% vs 16.2%, P＜0.0001) and sustained response to IFN (85.7% vs 2.9%, P＜0.0001).In multivariate analysis, ISDR in nonstructural (NS) 5A (OR=0.39, P＜0.0001) and N-terminal variable region (OR=0.51, P=0.039) was selected as the independent predictors for small viral load, and ISDR (OR=39.0, P＜0.0001) was selected as the only independent predictor for sustained response.CONCLUSION: The N-terminal variable region in the C-terminal part of E2 correlates with both response to IFN monotherapy and viral load and is one of the factors independently associated with a small viral load.