Chronic hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) is a primary indication for liver transplantation (LT). In western countries, the estimated rate of HCC recurrence following LT is between 15% and 20% and is a major cause of mortality. Currently, there is no standard method to treat patients who are at high risk for HCC recurrence. The aim of this study was to investigate the molecular signatures underlying HCC recurrence that may lead to future studies on gene regulation contributing to new therapeutic options. Two groups of patients were selected, one including patients with HCV who developed HCC recurrence (HCC-R) ≤3 years from LT and the second group including patients with HCV who did not have recurrent HCC (HCC-NR). Microarray analysis containing more than 29,000 known genes was performed on formalin-fixed-paraffin-embedded (FFPE) liver tissue from explanted livers. Gene expression profiling revealed 194 differentially regulated genes between the two groups. These genes belonged to cellular networks including cell cycle G1/S checkpoint regulators, RAN signaling, chronic myeloid leukemia signaling, molecular mechanisms of cancer, FXR/RXR activation and hepatic cholestasis. A subset of molecular signatures associated with HCC recurrence was found. The expression levels of these genes were validated by quantitative PCR analysis.