Background: Bovine viral diarrhea virus (BVDV) is an endemic virus of North American cattle populations with significant economic and animal health impacts. While BVDV infection has a myriad of clinical manifestations, a unique and problematic outcome is the establishment of a persistently infected (PI) animal following in utero viral infection. While it is well established that PI animals serve as a constant reservoir of BVDV, the mechanism for the maintained infection remains unknown despite multiple theories. Objective: The purpose of this study was to use transcriptome analysis to investigate the long-term immune status of adult PI cattle and offer insight into the potential mechanistic establishment of persistent BVDV infection. Methods: Peripheral blood mononuclear cells were collected from PI beef cattle (N = 6) and controls (N = 6) for targeted RNAseq analysis using 54 immune-related genes followed by pathway enrichment analysis. Results: Analysis revealed 29 differentially expressed genes (FDR < 0.05, fold change ≥ 2), representing 14 significant KEGG pathways between groups (FDR < 0.05). Transcriptome changes indicated chronic upregulation of interferon-gamma (IFNG) with an unexpected expression of related genes. Conclusions: These results provide novel insight into understanding the adult PI immune system and indicate maintained stimulation resulting from virus-mediated dysregulation.