BACKGROUND: A 'thin' fibrous cap atheroma is the typical morphological characteristic of vulnerable plaque. Yet the very pathological studies that have provided these descriptions have also shown the actual prediction of plaque rupture to be rather less exact. Other relevant characteristics must be involved in the mechanisms of plaque rupture--blood pressure loading (P) and the material properties of the soft atheromatous core--as predictors of the distribution of the peak circumferential stress (PCS) locations. METHODS AND RESULTS: We used a computational structural analysis based on three typical in-vivo intravascular ultrasound images of fibrous cap atheroma in which we decreased the cap thickness (CTh). With different soft atheromatous core Young's moduli (Ecore), 414 simulations were performed under eight different physiological loading blood pressures. The transition from plaque stability to plaque instability was defined by a threshold of 300 kPa and is a feature of vulnerability. It was found that (1) irrespective of plaque geometry and composition, CTh < 60 microm exposed the plaque to PCSs in excess of 300 kPa; (2) the exponential variations in PCS with change in CTh and Ecore values show that very slight structural changes are enough to tilt a vulnerable plaque from stability to instability or vice versa; and (3) the relationship between P and PCS is proportional with P acting as trigger or as protector. CONCLUSION: The present study shows why, in clinical practice, mere morphological detection by imaging techniques of thin-cap fibro-atheroma is not in itself enough for the prediction of future rupture.