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Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) that affects cervid species throughout North America. We evaluated gene expression in white‐tailed deer collected by Illinois Department of Natural Resource wildlife managers during annual population reduction (e.g., sharpshooting) and disease monitoring efforts throughout the CWD‐endemic area of northcentral Illinois. We conducted comparative transcriptomic analysis of liver and retropharyngeal lymph node tissue samples between CWD‐positive (n = 5) and CWD‐not detected (n = 5) deer. A total of 74,479 transcripts were assembled, and 51,661 (69.36%) transcripts were found to have matched proteins in NCBI‐NR and UniProt. Our analysis of functional categories showed 40,308 transcripts were assigned to at least one Gene Ontology term and 37,853 transcripts were involved in at least one pathway. We identified a total of 59 differentially expressed genes (DEGs) in CWD‐positive deer, of which 36 and 23 were associated with liver and retropharyngeal lymph node tissues, respectively. Functions of DEGs lend support to previous relationships between misfolded PrP and cellular membranes (e.g., STXBP5), and internal cellular components. We identified several genes that suggest a link between CWD and retroviruses and identified the gene ADIPOQ that acts as a tumor necrosis factor (TNF) antagonist. This gene may lead to reduced production of TNF and impact disease progression and clinical symptoms associated with CWD (i.e., wasting syndrome). Use of candidate genes identified in this study suggests the activation of endogenous processes in CWD‐positive deer, which in turn may enable earlier detection of the disease. [ABSTRACT FROM AUTHOR]