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We examined the tissue response to subcutaneous injections of particulate polymethylmethacrylate powder in fully immunocompetent C3Hf/Sed mice as well as three strains of mice with different levels of lymphocyte dysfunction. Five weeks after the injection, we found clearly demarcated granulomas. Histological and immunohistochemical studies showed that these granulomas were similar among all strains, with either paucity or absence of lymphoid cells. In situ hybridization with use of complementary RNA probes indicated that macrophages were synthesizing interleukin-1beta messenger RNA (mRNA), a marker of macrophage activation, and a cytokine implicated in pathological bone resorption. We concluded that, in mice, there is a lymphocyte-independent pathway of macrophage activation in response to particulate polymethylmethacrylate. This suggests that the foreign-body response to particulate orthopaedic biomaterials is macrophage-initiated and maintained and that lymphocytes are not essential to this response, although they may modulate it.The mammalian response to particulate biomaterials does not appear to fit a specific immune hypersensitivity response; rather, it seems to follow a non-specific pattern of macrophage phagocytosis, activation, and cellular response to monokine release. Differences in the response to debris among patients, manifested by differences in the rapidity and extent of osteolysis around joint prostheses, are more probably related to factors other than the hypersensitivity response, such as the amount of particles released, individual differences in macrophage activation, or intracellular damage created by the particles after phagocytosis.