Calcium phosphate (CaP) crystals are a natural component of bone, but are also commonly found in other tissues in association with ageing and several diseases including atherosclerosis, medial calcification (Mönckeberg’s sclerosis), arthritis and cancer. The amount of CaP crystals deposited in arteries correlates positively with atherosclerotic plaque rupture and myocardial infarction but whether the crystals actively participate in driving the disease is unclear. The damaging effect of nano- and microparticulate CaP crystals in arthritic joints has been known for some time, and small CaP crystals occur in regions of atherosclerotic plaque stress and rupture. Since vascular smooth muscle cells (VSMCs) have a protective role in plaque rupture, we investigated whether CaP crystals could affect VSMC function. Adding either synthetic CaP crystals or calcified particles extracted from human atherosclerotic plaques to human aortic VSMCs in culture induced cell death, with the synthetic crystals being more potent than the plaque-extracted crystals. To investigate the mechanism of cell death, intracellular calcium ion levels were measured using video imaging of Fura-2-loaded cells. CaP crystals caused rapid rises in intracellular calcium ion concentration preceding cell death. Both effects were inhibited when lysosomal acidification was blocked with bafilomycin A, implicating lysosomal involvement in calcium signalling and cell death. Video imaging of VSMCs indicated that CaP crystals induce the formation of large plasma membrane blebs prior to cell death, suggesting focal sites of plasma membrane damage. Transmission electron microscopy revealed that CaP crystals adhered to the plasma membrane within 5 minutes of addition of crystals, with crystals individually aligning with the membrane or grouped in clusters at sites of profound plasma membrane fragmentation. VSMCs did not die until approximately 30 minutes after addition of CaP crystals (measured using propidium iodide uptake), which implies that the initial plasma membrane damage does not kill cells, but rather that cells make an attempt to repair/extrude damaged components. However, continued exposure to crystals overwhelms repair and calcium homeostatic mechanisms resulting in cell necrosis. Further studies suggest that CaP-binding proteins such as fetuin and albumin, that are known to bind to CaP crystals in vivo, may dampen the toxic effects of CaP on VSMCs. The coating of plaque-derived CaP crystals by these proteins could explain why they are less potent than synthetic CaP crystals in causing VSMC death. Uncovering how CaP crystals bind to VSMCs, induce damage, activate repair mechanisms, induce calcium signalling and involve key cellular organelles to result in necrosis may provide strategies to limit their damaging effects in the vessel wall.