Hepatitis C virus (HCV) is the causative agent of most cases of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) affecting more than 170 million people world‐wide. Progress in elucidating the nature of HCV and the development of new therapeutic strategies is hampered fundamentally by the absence of adequate small animal models simulating natural HCV infection. The creation of conditional mouse lines with the tetracycline‐controlled gene expression system holds new perspectives for simulation of wild‐type HCV infection in a small animal model. Transgenic mice were established with tetracycline‐inducible coexpression of HCV core or HCV open reading frame (ORF) and luciferase. In long‐term induction experiments, mice were examined for immunopathological changes after expression of HCV proteins. Inducible and liver‐specific expression of transgenes was detected by Western blot, immunoprecipitation, luciferase assay and in vivo imaging of bioluminescence of luciferase in genetically modified mice. Ectopic expression levels were determined quantitatively in the liver, kidney, heart and spleen of mice in the induced and non‐induced state. During long‐term induction an elevation of aminotransaminases (ALT) was observed only in HCV core/ORF‐expressing mice, but HCV‐specific immune response was not confirmed by in vitro immunological assays. The histology of liver sections provided evidence of steatosis, which was correlated with an inflammatory response. The inducible HCV‐transgenic mouse lines provide further evidence of liver pathogenesis in the presence of inflammation during liver‐specific expression of HCV proteins and offer new insights into the effects of temporally and spatially controlled protein expression of HCV. J. Med. Virol. 79: 1103–1112, 2007. © 2007 Wiley‐Liss, Inc.