Histopathological evaluation of the liver via biopsy remains the standard procedure for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in hepatitis C virus-positive recipients because of changes in common and overlapping with RHC. The aim of this study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 hepatitis C virus-positive recipients. The clinicopathological diagnosis based on biopsy examination was ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC without ACR (non-ACR group) in 13. Using oligonucleotide microarrays, we compared the transcriptional changes in the 2 groups and selected 2206 genes that were significantly modulated in ACR. We analyzed the regulatory networks in ACR with Ingenuity Pathway Analysis software, and we confirmed with quantitative real-time polymerase chain reaction the reproducibility of caspase 8, apoptosis-related cysteine peptidase and bone morphogenetic protein 2 up-regulation in another group of validation samples, representing 2 genes from the core network as the target genes for ACR. Our results demonstrated novel transcriptome patterns for ACR with concurrent RHC that were distinct from those of recipients with only RHC, suggesting that gene expression profiling may be useful in the diagnosis of ACR in recipients with hepatitis C.