Background <p>Capsule formation in contact with silicone implants may vary according to the administration of systemic immunosuppressive drugs.</p> Methods <p>A total of 18 Sprague-Dawley rats that underwent premuscular plane silicone implant insertion were divided into three groups as follows: Group 1, untreated negative control (<i>n</i> = 6); Group 2, treated with tacrolimus (<i>n</i> = 6); and Group 3, treated with dexamethasone as a positive control (<i>n</i> = 6). At 3 months after surgery, the histology and immunochemistry of the capsule tissues were analyzed.</p> Results <p>Systemic administration of dexamethasone and tacrolimus successfully reduced capsule thickness and inflammatory marker levels. The aggregation of CD3 (T lymphocytes)- and CD68 (histiocytes)-positive cells around the capsule also reduced.</p> Conclusions <p>This study aimed to evaluate whether systemic immunosuppression with tacrolimus modulates peri-implant capsule formation and key inflammatory/fibrotic pathways in a rat silicone implant model. We focused on histologic capsule thickness and immunohistochemical markers representing innate/adaptive immune activation and myofibroblast-driven fibrosis as surrogate measures of early periprosthetic tissue remodeling.</p> No Level Assigned <p>This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors <a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>