I study the stability of off-center low-density more or less spherical (fat) bubbles in clusters of galaxies and in planetary nebulae (PNs) to Rayleigh–Taylor (RT) instability. As the bubble expands and decelerates, the interface between the low-density bubble’s interior and the dense shell formed from the accreted ambient medium is RT-stable. If, however, in a specific direction the density decreases such that this segment is accelerated by the pressure inside the bubble, then this accelerated region is RT-unstable. The outermost region, relative to the center of the system, is the most likely to become unstable because there the density gradient is the steepest. Using simple analytical analysis, I find that off-center fat bubbles in PNs are much less stable than in clusters. In PNs bubbles become unstable when they are very small relative to their distance from the center; they can be stabilized somewhat if the mass loss rate from the stellar progenitor decreases for a time, such that the negative density gradient is much shallower. In clusters fat bubbles become unstable when their size is comparable to their distance from the center. I discuss some implications of this instability in clusters and in PNs.