BACKGROUND: The liver disease expression in chronic hepatitis C patients is variable and may partially depend on the sequence of the infecting viral genotype. AIM: To identify some hepatitis C virus (HCV) genotype-specific virus-host interactions potentially leading to clinically significant consequences. METHODS: We compared the gene expression profile of Huh-7 cells transiently expressing the core protein of HCV genotype 1b and 3a using microarray technology. RESULTS: Thirty-two genes were overexpressed in Huh-7 transfected with the HCV genotype 1b core protein and 57 genes in cells transfected with the genotype 3a core protein. On the other hand, we found 20 genes downregulated by core 1b and 31 genes by core 3a. These included genes involved in lipid transport and metabolism, cell cycle, immune response and insulin signalling. CONCLUSION: The expression of HCV core proteins of different genotypes leads to a specific gene expression profile. This may account for the variable disease expression associated with HCV infection.