Background Rapid fibrovascularization and a moderate inflammatory response are considered as prerequisites for a successful engraftment of porous polyethylene (PPE) implants. Plasmin is the principal effector protease in the fibrinolytic system and has recently been implicated in tissue integration of biomaterials. Tissue plasminogen activator (tPA) is the main plasminogen activating protease, whose activity is tightly controlled by plasminogen-activator inhibitor-1 (PAI-1). So far, the functional relevance of tPA and PAI-1 for the engraftment of biomaterials remains largely unclear. Materials and Methods Using in vivo fluorescence microscopy, vessel density and leukocyte-endothelial cell interactions were evaluated on days 7, 10, and 14 after implantation of PPE implants in dorsal skinfold chambers in wild-type, tPA-/-, or PAI-1-/- mice. Tissue integration was analyzed on day 14 by measuring the force needed for mechanical removal of the implant out of the host tissue. Collagen deposition within the implant was assessed by second-harmonic imaging microscopy. PPE implants coated with recombinant or modified proteins were analyzed in a separate set of experiments. All surgical procedures were performed under anesthesia with ketamine (75 mg/kg b.w. i.p.) and xylazine (25 mg/kg b.w. i.p.). For statistical analysis, the ANOVA on ranks test followed by the Student-Newman-Keuls test was used. Results Vessel density and leukocyte-endothelial cell interactions in the host tissue did not significantly differ among experimental groups. In contrast, vessel density and leukocyte-endothelial cell interactions in the implant on days 7 and 10 after implantation as well as collagen deposition within the implant were significantly diminished in tPA- or PAI-1-deficient animals. Moreover, mechanical integration of the implant material was significantly attenuated in tPA or PAI-1 deficient animals. Conversely, surface coating with recombinant tPA or PAI-1 significantly accelerated implant vascularisation in wild-type mice, while leukocyte-endothelial cell interactions in the implant or the host tissue as well as mechanical integration of the implant were not significantly altered. Surface coating with a tPA mutant lacking its enzymatic activity did not significantly improve implant vascularisation. Conclusions Endogenous tPA and PAI-1 promote functional tissue integration of PPE biomaterial through effects on implant fibrovascularisation. In this context, tPA is thought to mediate these effects largely via its proteolytic properties. As a clinical perspective, surface coating with recombinant tPA or PAI-1 might provide a novel strategy for accelerating the vascularisation of PPE implants under unfavorable conditions for implantation.