Compression of arsenolite has been studied from a joint experimental and theoretical point of view. Experiments on this molecular solid at high pressures with different pressure-transmitting media have been interpreted thanks to state-of-the-art ab initio calculations. Our results confirm arsenolite as one of the most compressible minerals and provide evidence for ordered helium trapping above 3 GPa between adamantane-type As 4 O 6 cages. Our calculations indicate that, at relatively small pressures, helium establishes rather localized structural bonds with arsenic forming a compound with stoichiometry As 4 O 6 · 2He. All properties of As 4 O 6 · 2He are different from those of parent As 4 O 6 . In particular, pressure-induced amorphization, which occurs in arsenolite above 15 GPa, is impeded in As 4 O 6 · 2He, thus resulting in a mechanical stability of As 4 O 6 · 2He beyond 30 GPa. Our work paves the way to explore the formation of alternative compounds by pressure-induced trapping and reaction of gases, small atomic or molecular species, in the voids of molecular solids containing active lone electron pairs. DOI: 10.1103/PhysRevB.93.054102Molecular solids are very soft materials with openframework structures composed of molecular units, exhibiting strong covalent interatomic forces, which are linked by weak intermolecular forces, such as van der Waals interactions or hydrogen bonding forces. Pressure is a thermodynamic variable that allows tuning interatomic distances and consequently is a powerful tool to study atomic interactions and the connectivity of different molecular units -hence, the possibility of molecular solids to trap small atoms or molecules. In this sense, molecule trapping has received a lot of interest from the scientific community due to its potential industrial applications covering hydrogen storage [1] and CO 2 segregation from other organic compounds [2], among others. Recently, the small size of helium has triggered the study of pressure-induced helium trapping and how this effect affects the compressibility of host compounds. Those first studies were focused on helium trapping in silica glass [3][4][5] that is an amorphous compound with disordered interstitial voids large enough to host and trap helium. However, more studies need to be made of pressure-induced helium trapping in ordered crystallographic compounds, such as molecular solids.Helium reaction is a challenge since it is one of the most inert elements in nature [6]. Previous studies of helium trapping in glasses have not revealed the pressure-induced reactivity of helium with the glass structure. On the search of the formation of solid structures with helium, the study of * juasant2@upv.es † fjmanjon@upv.es mixtures of helium with other noble gases at high pressures has exhibited successful results. The mix of those fluids under pressure allows the formation of solid van der Waals compounds with exotic stoichiometries [7,8] [He(N 2 ) 11 , Ne(He) 2 ] given by the solubility of helium and dominated by the crystallization proces...