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)-lb-infected patients treated with IFN. METHODS: The C-terminal part of E2 (codons 617-711) including PKR/eIF2a 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 E2 was 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. 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 ) -lb-infected patients treated with IFN. METHODS: The C-terminal part of E2 (codons 617-711) including PKR / eIF2a phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-lb- infected patients treated by IFN monotherapy. RESULTS: The amino acid substitutions in PePHD detected only 4 of 85 patients were not correlated either with IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C -terminal part of E2 was 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) 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 NS with OR = 0.39, 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.