Corynebacterium pseudotuberculosis (Cp) is the etiological agent of caseous lymphadenitis, which has a detrimental impact on the health of small ruminants. The study’s goals were the characterization of the ovine whole blood transcriptome and functional comparison of the differentially expressed genes between healthy and affected animals. The blood samples of East Frisian sheep were obtained from Cp serologically positive (3) and negative ewes (3) and the health controls (3) of another herd. Differential gene expression was analyzed by RNA-seq on an Illumina NextSeqTM 550 system using the DESeq2 approach. The DEG sets were annotated with UniProt Knowledgebase and the WEB-based GEne SeT AnaLysis Toolkit.