The factors responsible for atherosclerotic plaque rupture, the initiating event in the majority of acute coronary syndromes, have received a lot of attention in recent times. However, the effect of calcification on plaque vulnerability is still a matter of considerable debate. In order to clarify the effect of calcification on plaque stresses and vulnerability, parametric "what if" studies were conducted on a histology specimen of a coronary endarterectomy plaque using finite element analysis and the biomechanical stresses calculated. It was found that the maximum principle stresses may decrease, increase, or remain unchanged depending on the location of calcification within a plaque and the lumen shape. The effect of calcification on plaque stresses in a lipid-rich plaque is a consequence of a complex interplay of a number of factors including vessel geometry, lipid distribution, and patterns and site of calcification. © 2013 Copyright Taylor and Francis Group, LLC.