Prion diseases are a class of transmissible fatal disorders. In order to identify alterations associated with the pathogenesis of prion diseases, several studies have been conducted involving differential gene expression analysis using cDNA libraries, mRNA differential displays, and gene microarrays. These genomic approaches may be useful for identifying genes that are differentially expressed in prion diseases and that may participate directly or indirectly in the pathogenesis of the disease. In this study, we compared the gene expression profiles of normal and CWD-infected TgElk mice using the GeneFishing differentially expressed gene (DEG) screening system and real-time PCR analysis. DEGs were screened using the ACP-based PCR method with GeneFishing synthesis. In order to validate candidate genes, we used quantitative PCR (qPCR), and eleven DEGs were identified. Five of these eleven DEGs were upregulated and two were downregulated in the CWD mice. The DEGs newly identified in this study may be useful for diagnosing and studying the pathogenesis of prion diseases.