The clinical manifestations of chronic hepatitis B (CH‐B) and chronic hepatitis C (CH‐C) are different. We previously reported differences in the gene expression profiles of liver tissue infected with CH‐B or CH‐C; however, the signaling pathways underlying each condition have yet to be clarified. Using a newly constructed cDNA microarray consisting of 9614 clones selected from 256,550 tags of hepatic serial analysis of gene expression (SAGE) libraries, we compared the gene expression profiles of liver tissue from 24 CH‐B patients with those of 23 CH‐C patients. Laser capture microdissection was used to isolate hepatocytes from liver lobules and infiltrating lymphoid cells from the portal area, from 16 patients, for gene expression analysis. Furthermore, the comprehensive gene network was analyzed using SAGE libraries of CH‐B and CH‐C. Supervised and nonsupervised learning methods revealed that gene expression was correlated more with the infecting virus than any other clinical parameters such as histological stage and disease activity. Pro‐apoptotic and DNA repair responses were predominant in CH‐B with p53 and 14‐3‐3 interacting genes having an important role. In contrast, inflammatory and anti‐apoptotic phenotypes were predominant in CH‐C. These differences would evoke different oncogenic factors in CH‐B and CH‐C. In conclusion, we describe the different signaling pathways induced in the livers of patients with CH‐B or CH‐C. The results might be useful in guiding therapeutic strategies to prevent the development of hepatocellular carcinoma in cases of CH‐B and CH‐C. (HEPATOLOGY 2006;44:1122–1138.)