The response of murine macrophages to clinically relevant polyethylene wear particles generated from different polyethylenes at various time points and volumetric doses in vitro was evaluated. Clinically relevant ultra high molecular weight polyethylene (UHMWPE) wear debris was generated in vitro in a lubricant of RPMI 1640 supplemented with 25% (v/v) foetal calf serum using a multi-directional pin-on-plate wear rig under sterile conditions. Wear debris was cultured with C3H murine peritoneal macrophages at various particle volume (microm(3)): cell number ratios. The secretion of TNF-alpha was determined by ELISA. Initially the effect of molecular weight of UHMWPE was considered. Higher molecular weight GUR415HP was shown to have a lower wear rate than the lower molecular weight GUR1120, however a greater volume of the wear debris produced by the high molecular weight GUR415HP was in the 0.1-1.0 microm size range. Wear debris from GUR415HP produced significant levels of TNF-alpha at a concentration of 1 microm(3)/cell while at least 10 microm(3)/cell of GUR1120 wear debris per cell was needed to produce significant levels of TNF-alpha. Secondly the effects of crosslinking GUR1050 was examined when worn against a scratched counterface. The wear rate of the material was shown to decrease as the level of crosslinking increased. However the materials crosslinked with 5 and 10 Mrad of gamma irradiation produced higher percentages of 0.1-1.0 microm size wear particles than the non-crosslinked material. While the crosslinked material was able to stimulate cells to produce significantly elevated TNF-alpha levels at a particle concentration of just 0.1 microm(3)/cell only concentrations of 10 microm(3)/cell and above of the non-crosslinked wear debris were stimulatory. When the counterface was changed from scratched to smooth the wear rate for all three GUR1050 materials was further reduced. For the first time nanometre size wear particles were observed from polyethylene which reduced the percentage mass of debris in the 0.1-1.0 microm size range. For all three materials on the smooth counterface only concentrations of 50 microm(3)/cell and above were stimulatory. This study has demonstrated that molecular weight, crosslinking and counterface roughness are important factors in determining the biological activity of polyethylene.