This work demonstrated a significant hydrogen isotopes permeation resistance in nitride nano-multilayer coatings. Dense and homogeneous CrN/AlTiN nano-multilayer coatings with different period-thicknesses were fabricated as hydrogen isotopes permeation barriers (HIPB) to highlight the effect of interface on hydrogen isotopes permeation resistance. Deuterium permeation measurement found that the nano-multilayer coatings had much higher permeation reduction factors (PRF) than the corresponding monolayer coatings, and more importantly there was an interface-number-dependent deuterium permeation resistance where the nano-multilayer coating containing more interfaces had higher PRF. Interfaces in the nano-multilayer coatings play a key role in the significant improved deuterium permeation resistance which was explained from three aspects. Ceramic nano- multilayer coatings offer a promising alternative for the design and preparation of HIPB in the hydrogen related fields. (C) 2020 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved.