The aim of the present study was to investigate the proteolytic potential and localization of matrix metalloproteinase (MMP)-2 in relation to its regulatory protein, membrane-type-MMP (MT1-MMP), and tissue inhibitor of metalloproteinase-2 (TIMP-2), as well as to clarify an important step in the cascade of periprosthetic connective-tissue remodeling in loose total-hip prostheses. Immunohistochemical analysis revealed increased expression of MT1-MMP, MMP-2, and TIMP-2 in fibroblasts, synovial lining-like cells, and endothelial cells, as well as, to some extent, in monocyte/macrophage-like cells in both tissues from the bone-implant interface and reactive cellular tissues from regenerating capsules in loose hip joints, when compared with control fibrous tissues between bone and implants retrieved from unloosened hip joints. In loose hip joints, reverse transcription-PCR analysis showed the presence of MT1-MMP, MMP-2, and TIMP-2 mRNA in both the bone-implant interface and regenerating capsular tissues. Increased protein levels of MMP-2 and TIMP-2 were also demonstrated by an ELISA, and those of MT1-MMP were shown by immunoblot analysis. Gelatin-zymographic analysis confirmed the presence of both pro- and active forms of MMP-2, which suggested the in situ activation of MMP-2 by MT1-MMP in the loose hip joints. Collectively, these data suggest that the MT1-MMP/MMP-2/TIMP-2 system participates in the extracellular matrix degradation and periprosthetic connective-tissue remodeling in loose hip joints, and may thus contribute to the periprosthetic weakening, loosening, and osteolysis that can occur around implants.