The Gram-negative bacterium Actinobacillus pleuropneumoniae is the etiologic agent of porcine contagious pleuropneumoniae, a lethal respiratory infectious disease causing great economic losses in the swine industry worldwide. In order to better interpret the genetic background of serotypic diversity, nine genomes of A. pleuropneumoniae reference strains of serovars 1, 2, 4, 6, 9, 10, 11, 12, and 13 were sequenced by using rapid high-throughput approach. Based on 12 genomes of corresponding serovar reference strains including three publicly available complete genomes (serovars 3, 5b, and 7) of this bacterium, we performed a comprehensive analysis of comparative genomics and first reported a global genomic characterization for this pathogen. Clustering of 26,012 predicted protein-coding genes showed that the pan genome of A. pleuropneumoniae consists of 3,303 gene clusters, which contain 1,709 core genome genes, 822 distributed genes, and 772 strain-specific genes. The genome components involved in the biogenesis of capsular polysaccharide and lipopolysaccharide O antigen relative to serovar diversity were compared, and their genetic diversity was depicted. Our findings shed more light on genomic features associated with serovar diversity of A. pleuropneumoniae and provide broader insight into both pathogenesis research and clinical/epidemiological application against the severe disease caused by this swine pathogen.Actinobacillus pleuropneumoniae, a Gram-negative facultative anaerobic encapsulated coccobacillus, belongs to the Actinobacillus genus of the Pasteurellaceae family (19). A. pleuropneumoniae is a primary bacterial etiologic agent of porcine contagious pleuropneumonia, a severe respiratory disease leading to great economic losses to the global swine industry (7). The cases usually display pleuropneumonia and pulmonary lesions characterized by serious hemorrhage and necrosis. To date, several factors involved in the virulence of A. pleuropneumoniae have been described, including Apx exotoxins, capsular polysaccharides (CPS), lipopolysaccharides (LPS), outer membrane proteins, iron-acquisition proteins and adhesin factors (11,19,24). However, the genetic differences of pathogenesis remain poorly characterized and are worth interpreting from the perspective of comparative genomics for this bacterium.Thus far, 15 serovars and two biotypes of A. pleuropneumoniae have been recognized, with great variations in virulence and interlocal distributions (6). The predominant serovar-specific antigens are composed of CPS, which could rigorously define serovars of A. pleuropneumoniae (6, 34). Antigenic differences in the LPS can further determine A. pleuropneumoniae subtypes within a same capsular serovar (13). The metabolic and virulent characteristics of this pathogen have been systematically described based on the prior knowledge and two complete genomes (18, 47), but the molecular basis and evolutionary mechanism of serotypic diversity are still not well explained due to the lack of sequence information. To invest...