AbstractParticulate debris, including that from polymethylmethacrylate (PMMA) cement, is observed commonly in the membrane surrounding loose joint prostheses. Such debris is assumed to cause an inflammatory response and contributes to osteolysis and failure of the implant. A subcutaneous rat air‐pouch model was used to assess quantitatively thein vivoeffects of the size, morphology, and surface area of PMMA particles on the acute inflammatory response. PMMA particles were divided into three groups. In Group A, mechanical grinding of cured bone cement produced irregularly shaped particles; Group B included spherical particles of PMMA powder (Simplex P); and Group C consisted of commercially prepared spherical latex particles. All three groups had two size distributions:<20 μm and 50–350 μm. For a given mass or dose, the small, irregularly shaped mechanically produced particles in Group A elicited a significantly greater inflammatory reaction than the large particles in Group A, as expressed by the release of tumor necrosis factor (TNF), neutral metalloprotease (NMP), and prostaglandin E2(PGE2) and the white blood cell (WBC) count within a 24‐hour period. Similar findings were seen in Group B. Particles in Group C were used to compare the effect of absolute numbers of large and small particles and surface area. Large (10–126 μm) spherical PMMA particles at a dose of 1.7 × 106particles/ml caused a significantly higher inflammatory response, as measured by WBC count and production of NMP and PGE2, than small (1–10 μm) spheres at a dose of 4 × 106particles/ml. However, the production of TNF in the rats was significantly increased with small particles (p<0.05) at a concentration 4‐fold less than that with the large particles (4 × 105compared with 1.7 × 106particles/ml). This finding may reflect a different cellular mechanism for the TNF component of the inflammatory response than is measured by WBC counts or by levels of PGE2and NMP. As the calculated surface area of the PMMA particles increased, a threshold level was reached, at which point the inflammatory response increased dramatically. The size of particles has a role in the prolongation and intensity of the release of specific cytokines. The total surface area of the particles appeared to be an important factor in determining the inflammatory response, as measured by WBC count,