Several investigators have suggested that biologic molecules adsorbed onto particles may play a key role in determining macrophage response. Adsorbed endotoxins (bacterial debris) may be of particular importance since they are widely present exogenously and endogenously and adhere strongly to many materials. Murine-transformed peritoneal macrophages (IC-21) were used in this in vitro study. Secretions of IL-1 beta, TNF alpha, and IL-6 were used as a measure of macrophage response to micron-range particles of high-density polyethylene and Co-Cr-Mo alloy, with and without adsorbed lipopolysaccharide (LPS) endotoxin. Little cytokine secretion was measured in response to particles (and to polypropylene experimental chambers) cleaned with ethanol and saline and not exposed to LPS. The lack of macrophage response to cleaned particles has been reported by others and may help reconcile conflicting reports in the literature. Cytokine secretion levels were high in all cases if the chambers (with or without particles) were exposed to LPS (and rinsed to minimize nonbound LPS). Secretion patterns were different with particles present and for polymer versus metal particles. Overall, these results suggest that (1) adsorbed molecules on material surfaces strongly affect macrophage response and (2) particle surface chemistry and microstructure affect the concentration and configuration of adsorbed molecules, further influencing particle interaction with macrophage surface receptors.