Dental implant success is based on the biologic integration of an alloplastic device in both endosseous and transmucosal tissues. The health of the transmucosal tissues adjacent to the implant and abutment are essential to success. Inflammation leading to alveolar bone loss (peri-implantitis) is a risk factor influencing a significant proportion of implants and patients. To better understand the molecular pathogenesis of peri-implantitis, a within patient comparison of gene expression within tissues at healthy and affected implants was performed using the Affymetrix Human ST1 gene array platform. RNAs isolated from tissues surrounding healthy and affected implants of 21 participants were evaluated. GeneSpring and IPA software revealed significant up-regulated genes related to inflammation, B-cell function and tissue detruction, and significant down regulated genes related to desmosome function and keratinized epithelium development and function. Peri-implantitis is associated with molecular changes that implicate epithelial barrier dysfunction as a potential key aspect of pathogenesis.