Plaque rupture and/or erosion are considered the leading cause of cardiovascular events. To elucidate this process, we demonstrated that during cholesterol crystallization the occupied volume increases rapidly and sharp-tipped crystals cut through thin biological membranes in their path. The amount of cholesterol correlated directly with both peak level and rate of crystal growth (r = 0.98; r = 0.99; p < 0.01, respectively). These observations suggest that crystallization of cholesterol in atherosclerotic plaques can induce cap rupture and/or erosion. Observations by scanning electron microscopy confirmed similar findings of cholesterol crystals perforating the lumen surface in human coronary artery segments with ruptured plaque.