Calcium pyrophosphate dihydrate (CPPD) crystals occur frequently in noninflammatory osteoarthritic joints; however, they can be phlogistic and membranolytic, causing acute pseudogout attack. So far, the molecular mechanism of crystal-induced membranolysis is still unclear. In this study, using the method of Chemistry at Harvard Macromolecular Mechanics (CHARMM) molecular dynamics, we show that the interactions between the surface of CPPD crystal and the extracellular layer of the hydrated dimyristoyl phosphatidylcholine (DMPC) phospholipid bilayer may lead to decoupling of the external layer from the intracellular side of the membrane. As a result, a local thinning of the layer on the intracellular side of the membrane occurs, which favors water penetration, leading to membranolysis.