Streptococcus suis is a bacterial swine pathogen causing substantial economic and health burdens to the pork industry. Mechanisms used by S. suis to colonize and cause disease remain unknown and vaccines and/or intervention strategies currently do not exist. Studies addressing virulence mechanisms used by S. suis have been complicated because different isolates can cause a spectrum of disease outcomes ranging from lethal systemic disease to asymptomatic carriage. The objectives of this study were to perform comparative genomic analyses of S. suis isolates that exhibit different pathogenic capacities to identify genomic attributes associated with virulent phenotypes. Nine genetically diverse strains isolated within the U.S. were chosen for whole genome sequence analysis and virulence assessment. S. suis strains ISU2614 and ISU1606 exhibited a high level of virulence with all pigs (5 out of 5) in each of these groups developing systemic clinical disease within 8 days post-challenge. S. suis strains ISU2714, ISU2660, and ISU2514 were moderately virulent with 3 out of 5 pigs challenged with ISU2714 developing neurologic signs and/or lameness, while only 2 out of 5 pigs challenged with ISU2660 developed lameness. 1 out of 5 pigs challenged with ISU2514 developed neurologic signs and 2 out of 5 developed lameness. S. suis strains ISU2414, ISU2812, ISU2912, and SRD478 were completely avirulent and all pigs in these groups remained healthy and exhibited no signs of clinical disease. Whole genome sequencing followed by comparative genomic analyses revealed several notable regions of difference, including regions encoding secreted and membrane-associated factors, which likely contributed to the spectrum of clinical disease observed. Collectively, these results provide a foundation for understanding the genomic attributes responsible for the spectrum of virulent phenotypes that exist among S. suis isolates.