AbstractWith isolated leukocytes, inhibiting complement reduced material‐induced leukocyte activation (CD11b) with polyethylene glycol modified polystyrene beads (PS‐PEG), but not with polystyrene beads (PS). The PS‐PEG beads (TentaGel™) were complement activating as measured by SC5b‐9 levels consistent with the sensitivity of these beads to leukocyte inhibition with complement inhibitors. Following contact with PS and PS‐PEG beads, isolated leukocytes in plasma and in the absence in platelets were found to significantly upregulate CD11b, while TF expression and exposure of phosphatidylserine remained at background levels. Complement inhibition by means of sCR1 partially reduced CD11b upregulation on PS‐PEG beads, but had no effect with PS beads. Pyridoxal‐5‐phosphate (P5P) was able to significantly reduce both CD11b upregulation and exposure of phosphatidylserine with PS‐PEG beads, although it did not appear to inhibit SC5b‐9 production. Pentamidine and NAAGA inhibited complement and were effective in reducing CD11b upregulation with both PS and PS‐PEG. However, they also had an inhibitory effect on leukocyte signaling mechanisms, precluding their utility for further study in this context. Leukocyte adhesion occurred to similar extents on both PS and PS‐PEG beads. While sCR1 and P5P blocked adhesion and activation (for adherent leukocytes) on PS‐PEG beads, they had no effect on leukocytes adherent to PS beads. The role of complement in leukocyte activation and adhesion was found to be material‐dependent. Thus, leukocyte‐material compatibility may be resolved by complement inhibition in some but not all cases. For these other materials (example here was PS), other mechanisms, such as fibrinogen adsorption and direct leukocyte release, may need exploitation to minimize leukocyte activation and adhesion. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005