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This study tested the hypothesis that selective opsonization of orthopedic implant biomaterial wear particles by human serum proteins influences monocyte\/macrophage activation. Serum protein binding to metallic, polymeric, and ceramic particles was determined by one\u2010dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS\u2010PAGE). Individual proteins bound to particles were subsequently identified using two\u2010dimensional SDS\u2010PAGE, microsequencing techniques, and SWISS\u2010PROT analysis. Effects of selective protein opsonization on particle\u2010induced monocyte\/macrophage activation were assessed by quantification of interleukin\u20101beta, interleukin\u20106, and tumor necrosis factor\u2010alpha release. Results from one\u2010dimensional gel analyses revealed distinct serum protein\u2010binding patterns specific for each material tested. Two\u2010dimensional gel analysis together with amino acid sequencing of the prominent protein species confirmed the presence of albumin and alpha\u20101\u2010antitrypsin bound to all particles tested. In contrast to the metallic particles, apolipoprotein was a major species associated with polymeric particles. Opsonization of PMMA particles with purified preparations of each of the identified proteins showed that albumin significantly enhanced particle\u2010induced monocyte\/macrophage activation. These data confirm orthopedic biomaterial specific binding of human serum proteins and demonstrate that albumin exacerbates particle\u2010induced monocyte\/macrophage activation. Alterations in the chemical and surface properties of orthopedic biomaterials to modulate protein interactions may improve implant longevity. \u00a9 2003 Wiley Periodicals, Inc. 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