Recent investigations indicate that innate immune “danger‐signaling” pathways mediate metal implant debris induced‐inflammatory responses, for example, NALP3 inflammasome. How the physical characteristics of particles (size, shape, and chemical composition) affect this inflammatory reactivity remains controversial. We examined the role of Cobalt–Chromium–Molybdenum (CoCrMo) alloy particle shape and size on human macrophage phagocytosis, lysosomal destabilization, and inflammasome activation. Round/smooth versus irregularly shaped/rough CoCrMo‐alloy particles of ∼1 and 6–7 µm diameter were investigated for differential lysosomal damage and inflammasome activation in human monocytes/macrophages. While spherical/smooth 1 µm CoCrMo‐alloy particles did not measurably affect macrophage IL‐1β production, irregular 1 µm CoCrMo‐alloy particles induced significant IL‐1β increases over controls. Both round/smooth particles and irregular CoCrMo‐alloy particles that were 6–7 µm in size induced >10‐fold increases in IL‐1β production compared to similarly shaped smaller particles (p < 0.05). Larger irregular particles induced a greater degree of intracellular lysosomal damage and a >3‐fold increase in IL‐1β versus similarly sized round/smooth particles (at an equal dose, particles/cell). CoCrMo‐alloy particle‐size‐induced IL‐1β production was dependent on the lysosomal protease Cathepsin B, further supporting lysosomal destabilization as causative in inflammation. Phagocytosable larger/irregular shaped particles (6 µm) demonstrated the greatest lysosomal destabilization (observed immunofluorescently) and inflammatory reactivity when compared on an equal dose basis (particles/cell) to smaller/spherical 1 µm particles in vitro. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1633–1642, 2013