Mannheimia haemolytica’s (MH) role in bovine pathogenesis is linked to serovar with serotypes 1 (S1) and 6 (S6) commonly isolated from pneumonic lesions in calves and serotype 2 (S2) being a commensal in the upper respiratory tract. Comparative genomics was conducted using eleven isolates from Canada, USA or France representing S1, S2 and S6, from healthy, diseased or dead cattle that had succumbed to bovine respiratory disease. Genomes were sequenced using 454 technology, assembled and then annotated using the Integrated Microbial Genomes platform. Contigs were aligned against reference genome MH M42548 and screened for prophage and toxin anti-toxin systems. The MH pan-genome contained 6394 genes: 1716 core and 4678 accessory. The S1 and S6 core genomes harbored 357 and 263 more genes, respectively, than S2, most of unknown function. The number of prophages per genome ranged from 2-8 with 14 distinct bacteriophage genomes identified; 6 Mu-like, 6 lambda-like and 2 uncharacterized. Toxin-antitoxin systems are ubiquitous, but more prevalent in S1 and S6. All genomes contained a type I-C CRISPR-Cas system. CRISPR spacer diversity and organization was conserved among serotypes with 12-17 and 4-8 spacers in S1/S6 and S2 genomes, respectively. The majority of spacers originated from phage suggesting that, S1 and S6 strains may be more resistant to phage predation. All genomes contained T4SS and evidence of putative integrative conjugative elements (ICE). Three genomes harbored multi-drug resistance cassettes, likely associated with the ICE detected. There was no apparent relationship between genetic content, animal disease state and origin of the isolates examined. Multiple virulence factors were strongly correlated with serovar supporting the pathogenic phenotypes observed in S1 and S6 strains.