Intestinal colonization of the oral bacterium Haemophilus parainfluenzae has been associated with Crohn’s disease (CD) severity and progression. This study examines the role of periodontal disease (PD) as a modifier for colonization of H. parainfluenzae in patients with CD and explores the mechanisms behind H. parainfluenzae-mediated intestinal inflammation. Fifty subjects with and without CD were evaluated for the presence of PD, and their oral and fecal microbiomes were characterized. PD is associated with increased levels of H. parainfluenzae strains in subjects with CD. Oral inoculation of H. parainfluenzae elicits strain-dependent intestinal inflammation in murine models of inflammatory bowel disease, which is associated with increased intestinal interferon-γ (IFN-γ)+ CD4+ T cells and disruption of the host hypusination pathway. In summary, this study establishes a strain-specific pathogenic role of H. parainfluenzae in intestinal inflammation and highlights the potential effect of PD on intestinal colonization by pathogenic H. parainfluenzae strains in patients with CD. Display omitted •Haemophilus parainfluenzae elicits strain-dependent intestinal inflammation•Gut colonization of H. parainfluenzae is associated with increased IFN-γ+ CD4+ T cells•Periodontitis is associated with increased H. parainfluenzae in patients with Crohn’s disease Sohn et al. show differential pathogenicity of H. parainfluenzae strains and its potential association with periodontal disease in patients with Crohn’s disease.