The first High Kinetic Energy-Ion Mobility Spectrometry-Mass Spectrometry (HiKE-IMS-MS) studies involving six volatiles (acetone, acetonitrile, methanol, ethanol, 2-propanol, and 1-butanol) and their fully deuterated analogues are reported. The goal is to further our understanding of the ion–molecule chemistry occurring in the HiKE-IMS. This is needed for its full analytical potential to be reached. Product ions are identified as a function of the reduced electric field (30–115 Td) and the influence of sample air humidity in the reaction region on deuterium/hydrogen (D/H) exchange reactions is discussed. Reagent ions include H3O+(H2O)m (n = 0, 1, 2 or 3), NO+(H2O)n (m = 0 or 1) and O2+·. Reactions with H3O+(H2O)m lead to protonated monomers (through either proton transfer or ligand switching). Reactions with NO+ involve association with acetone and acetonitrile, hydride anion abstraction from ethanol, 2-propanol, and 1-butanol, and hydroxide abstraction from 2-propanol and 1-butanol. With the exception of acetonitrile, O2+· predominantly reacts with the volatiles via dissociative charge transfer. A number of sequential secondary ion-volatile processes occur leading to the formation of dimer and trimer-containing ion species, whose intensities depend on a volatile’s concentration and the reduced electric field in the reaction region. Deuterium/hydrogen (D/H) exchange does not occur for product ions from acetone-d6 and acetonitrile-d3, owing to their inert methyl functional groups. For the deuterated alcohols, rapid D/H-exchange reaction at the hydroxy group is observed, the amount of which increased with the increasing humidity of the sample air and/or lowering of the reduced electric field. Graphical abstract: [Figure not available: see fulltext.].