AbstractThe foreign body reaction (FBR) to biomaterials results in fibrous encapsulation. Excessive capsule fibrosis (capsular contracture) is a major challenge to the long‐term stability of implants. Clinical data suggests that the tissue type in contact with silicone breast implants alters susceptibility to developing capsular contracture; however, the tissue‐specific inflammatory and fibrotic characteristics of capsule have not been well characterized at the cellular and molecular level. In this study, 60 breast implant capsule samples are collected from patients and stratified by the adjacent tissue type including subcutaneous tissue, glandular breast tissue, or muscle tissue. Capsule thickness, collagen organization, immune and fibrotic cellular populations, and expression of inflammatory and fibrotic markers is quantified with histological staining, immunohistochemistry, and real‐time PCR. The findings suggest there are significant differences in M1‐like macrophages, CD4+ T cells, CD26+ fibroblasts, and expression of IL‐1β, IL‐6, TGF‐β, and collagen type 1 depending on the tissue type abutting the implant. Subglandular breast implant capsule displays a significant increase in inflammatory and fibrotic markers. These findings suggest that the tissue microenvironment contributes uniquely to the FBR. This data could provide new avenues for research and clinical applications to improve the site‐specific biocompatibility and longevity of implantable devices.