Arcobacter butzleri is a food and waterborne bacteria and an emerging human pathogen, frequently displaying a multidrug resistant character. Still, no comprehensive genome-scale comparative analysis has been performed so far, which has limited our knowledge on A. butzleri diversification and pathogenicity. Here, we performed a deep genome analysis of A. butzleri focused on decoding its core-and pan-genome diversity and specific genetic traits underlying its pathogenic potential and diverse ecology. In total, 49 A. butzleri strains (collected from human, animal, food and environmental sources) were screened.A. butzleri (genome size 2.07-2.58 Mbp) revealed a large open pan-genome with 7474 genes (about 50% being singletons) and a small core-genome with 1165 genes. The core-genome is highly diverse (≥55% of the core genes presenting at least 40/49 alleles), being enriched with genes associated with housekeeping functions. In contrast, the accessory genome presented a high proportion of loci with an unknown function, also being particularly overrepresented by genes associated with defence mechanisms. A. butzleri revealed a plastic virulome (including newly identified determinants), marked by the differential presence of multiple adaptationrelated virulence factors, such as the urease cluster ureD(AB)CEFG (phenotypically confirmed), the hypervariable hemagglutinin-encoding hecA, a putative type I secretion system (T1SS) harboring another agglutinin potentially related to adherence and a novel VirB/D4 T4SS likely linked to interbacterial competition and cytotoxicity. In addition, A. butzleri harbors a large repertoire of efflux pumps (EPs) (ten "core" and nine differentially present) and other antibiotic resistant determinants. We provide the first description of a genetic determinant of macrolides resistance in A. butzleri, by associating the inactivation of a TetR repressor (likely regulating an EP) with erythromycin resistance. Fluoroquinolones resistance correlated with the Thr-85-Ile substitution in GyrA and ampicillin resistance was linked to an OXA-15-like β-lactamase. Remarkably, by decoding the polymorphism pattern of the porin-and adhesin-encoding main antigen PorA, this study strongly supports that this pathogen is able to exchange porA as a whole and/or hypervariable epitope-encoding regions separately, leading to a multitude of chimeric PorA presentations that can impact pathogen-host interaction during infection. Ultimately, our unprecedented screening of short sequence repeats detected potential phasevariable genes related to adaptation and host/environment interaction, such as lipopolysaccharide modification and motility/chemotaxis, suggesting that phase variation likely modulate A. butzleri key adaptive functions.In summary, this study constitutes a turning point on A. butzleri comparative genomics revealing that this human gastrointestinal pathogen is equipped with vast virulence and antibiotic resistance arsenals, which, coupled with its remarkable core-and pan-genome diversity, opens a multitude of ...