Wear of polyethylene causes loosening of joint prostheses because of the particle mediated activity of the host tissue. It was hypothesized that conventional and crosslinked polyethylene particles lead to similar biological effects around the knee joint in vivo as well as to a similar particle distribution in the surrounding tissues. To verify these hypotheses, particle suspensions of six different polyethylene materials were injected into knee joints of Balb/C mice and intravital microscopic, histological and immunohistochemical evaluations were done after 1 week. Whereas the biological effects on the synovial layer and the subchondral bone of femur and tibia were similar for all the polyethylenes, two crosslinked materials showed an elevated cytokine expression in the articular cartilage. Furthermore, the distribution of particles around the joint was dependent on the injected polyethylene material. Those crosslinked particles, which remained mainly in the joint space, showed an increased expression of TNF-alpha in articular cartilage. The data of this study support the use of crosslinked polyethylene in total knee arthroplasty. In contrast, the presence of certain crosslinked wear particles in the joint space can lead to an elevated inflammatory reaction in the remaining cartilage, which challenges the potential use of those crosslinked polyethylenes for unicondylar knee prostheses.