BACKGROUND & AIMS: To determine whether amino acid mutations in the core region of hepatitis C virus (HCV) genotype 1 are associated with response to interferon (IFN) therapy and development of hepatocellular carcinoma (HCC). METHODS: We followed up 361 patients (median duration, 121months), and IFN monotherapy was administered to 275 (76%) [sustained virological response (SVR) rate, 26.5%]. Using pretreatment sera, mutations at core residues 70 and 91 were analyzed [double wild (DW)-type amino acid pattern: arginine, residue 70; leucine, residue 91]. RESULTS: A low aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and low HCV load were independently associated with SVR, but core mutations were not. During follow-up, 12 of 81 (14.8%) patients with the DW-type pattern and 52 of 216 (24.1%) patients with non-DW-type pattern developed HCC (p=0.06, Breslow-Gehan-Wilcoxon test). Multivariate analysis with the Cox proportional-hazards model revealed the following independent risk factors for HCC: male gender [p<0.0001; risk ratio (RR), 3.97], older age (p<0.05; RR, 2.08), advanced fibrosis (p<0.0001; RR, 5.75), absence of SVR (p<0.01; RR, 10.0), high AST level (p<0.01; RR, 2.08), high AST/ALT ratio (p<0.01; RR, 2.21), and non-DW-type pattern (p<0.05; RR, 1.96). In patients with F0-F2 fibrosis at entry, non-DW-type was likely to lead to cirrhosis (p=0.051). CONCLUSIONS: In HCV genotype 1 patients, HCC risk could be predicted by studying core mutations, response to IFN, and host factors like age, gender, and liver fibrosis.