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Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of β2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis). Microbial communities in the local environment (subgingival plaque) are thought to be the triggers for inflammatory periodontitis, yet little is known regarding the microbial communities associated with LAD-I periodontitis. Here we present the first comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, and investigate the relationship of this tooth adherent microbiome to the local immunopathology of periodontitis. We show that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitits. Select periodontitis-associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. We suggest that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. We demonstrate that bacterial LPS translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. We also show in in vitro assays with human macrophages and in vivo in animal models that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis., Author Summary Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency resulting from gene mutations in the CD18 subunit of β2 integrins that lead to defective neutrophil adhesion and transmigration into tissues. Affected patients suffer from recurrent life threatening infections and from a severe form of the oral disease periodontitis. The setting of this rare monogenic immune disorder provides a unique opportunity to explore consequences of defective neutrophil tissue transmigration on immunity and microbial colonization in barrier sites such as the oral mucosa. Furthermore, characterization of the oral- subgingival microbiome in LAD expands our understanding of LAD periodontitis, an aggressive disease which is recalcitrant to treatment and often leads to loss of the entire dentition in adolescence. Our current studies in a cohort of LAD patients show that the subgingival microbiome in LAD- periodontitis is unique in its composition and differs from that of health and aggressive periodontitis. Notably our studies reveal that the subgingival communities of LAD can serve as initial triggers for local immunopathology through translocation of bacterial products into tissues and stimulation of local IL-23-related destructive inflammatory responses.