Tissue transglutaminase 2 (TG2) is ubiquitously expressed in normal tissues and plays an important role in the pathophysiology of wound healing. An increase in periodontal tissues has been previously reported in cyclosporine-induced gingival overgrowth. Purpose: The aim of this study was to explore associations between TG2 expression and the vascularization and maturation processes of peri-implant soft tissues over time. Materials and Methods: Edentulous patients proposed for mandibular implant-retained overdentures were included in the study. Biopsies of the peri-implant mucosa were performed at the first surgical stage and at 4, 8, and 12 months after prosthetic load. A follow-up program was directed to record plaque indexes, bleeding on probing data, and pocket probing depth around implants. An evaluation of the vessels' density was carried out by digital virtual microscopy and using an immunohistochemistry approach (antibodies anti-CD31, anti-TG2). A robust multivariable regression model was implemented. Results: According to model results, blood vessel count and probing (as a marker of gingival overgrowth in absence of plaque) significantly decrease over time and are associated with TG2, particularly for values above the median. Conclusion: The association of an increased TG2 expression in the extracellular matrix might have a significant impact in the development of gingival overgrowth around a loaded implant.