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Background: The impact of S. enterica colonization in cattle is highly variable and often serovar-dependent. The aim of this study was to compare the global transcriptomes of highly pathogenic bovine-adapted S. enterica serovar Dublin and the less pathogenic, bovine-adapted, serovar Cerro during interactions with bovine epithelial cells, to identify genes that impact serovar-related outcomes of S. enterica infections in dairy animals. Result: Bovine epithelial cells were infected with S. enterica strains from serovars Dublin and Cerro, and the bacterial RNA was extracted and sequenced. The total number of paired-end reads uniquely mapped to non-rRNA and non-tRNA genes in the reference genomes ranged between 12.1 M (Million) and 23.4 M (median: 15.7 M). In total, 360 differentially expressed genes (DEGs) were identified with at least two-fold differences in the transcript abundances between S. Dublin and S. Cerro (false discovery rate ≤ 5%). The highest number of DEGs (17.5%, 63 of 360 genes) between the two serovars were located on the genomic regions potentially associated with Salmonella Pathogenicity Islands (SPIs). DEGs potentially located in the SPI-regions that were upregulated (≥ 2-fold) in the S. Dublin compared with S. Cerro included: 37 SPI-1 genes encoding mostly Type 3 Secretion System (T3SS) apparatus and effectors; all of the six SPI-4 genes encoding type I secretion apparatus (siiABCDEF); T3SS effectors and chaperone (sopB, pipB, and sigE) located in SPI-5; type VI secretion system associated protein coding genes (sciJKNOR) located in SPI-6; and T3SS effector sopF in SPI-11. Additional major functional categories of DEGs included transcription regulators (n = 25), amino acid transport and metabolism (n = 20), carbohydrate transport and metabolism (n = 20), energy production and metabolism (n = 19), cell membrane biogenesis (n = 18), and coenzyme transport and metabolism (n = 15). DEGs were further mapped to the metabolic pathways listed in the KEGG database; most genes of the fatty acid β-oxidation pathway were upregulated/uniquely present in the S. Dublin strains compared with the S. Cerro strains. Conclusions: This study identified S. enterica genes that may be responsible for symptomatic or asymptomatic infection and colonization of two bovine-adapted serovars in cattle. [ABSTRACT FROM AUTHOR]