Octa(aminopropylsilsesquioxane) Si8O12[(CH2)3NH2]8 is a very important precursor for many other hybrid organic/inorganic polyhedral oligomeric silsesquioxanes (POSS) because of the reactivity of its primary amine groups. Unfortunately, it is unstable in water, which can lead to the cleavage of its siloxane cage. In the present work, such a degradation was confirmed using solid-state 29Si NMR spectroscopy, and the molecular features at the basis of this instability were studied using molecular dynamics simulations (MD). It was also investigated whether replacing the primary amine end groups by secondary amines or by amides with long aliphatic chains could lead to an improvement in the water stability of the Si/O framework. In the pure bulk models, all POSS interdigitate with their pendant organic arms intertwined. Upon insertion of isolated molecules into water, the dimensions of the primary amine POSS remain close to those of the bulk, while the secondary amine and the amide POSS favor conformations that optimize the intramolecular chain–chain interactions. When there are several POSS molecules in water, they cluster with each other through both intra- and intermolecular chain–chain interactions. This tendency for the organic chains to intertwine whenever possible provides some protection to the siloxane cages from water, but also leaves some of the siloxane O exposed. As such, the latter are accessible to form transient hydrogen bonds with the water molecules, which could be a precursor step to hydrolysis and thus cage breakage. In the molecular models, a better protection was obtained in the amide POSS for two reasons: its chains tended to wrap efficiently around its cage, and its ketone O kept water from getting close to the siloxanes. The molecular modeling characterizations were found to agree very well with experimental evidence.