The thermally induced shape instability of Fe/Au, Fe/Ag, and Nb/Cu multilayer systems during heat treatments was investigated. The disintegration temperature of these systems decreases with decreasing single-layer thickness. Up to a critical thickness, the disintegration temperature is proportional to the reciprocal layer thickness. The driving force of this process is related to the interfacial stress and the local variation of the interface curvature. After heat treatment, spherically shaped Fe and Nb nanoparticles, located in chains perpendicular to the substrate, were observed and depicted by means of transmission electron microscopy (TEM) and X-ray microscopy (XRM).