Interface stress is a fundamental descriptor for interphase boundaries and is defined in strict relation to the interface energy. In nanomultilayers with their intrinsically high interface density, the functional properties are dictated by the interface structure, which is governed by the delicate interaction of residual interface and volume stresses. In the present work, experimental estimations of the interface stress in Cu/W NMLs were compared with corresponding theoretical values as calculated using DFT (adopting an incoherent bcc W{110}/fcc Cu{111} interface with variable in -plane strain). The Cu/W interface stress was experimentally tuned monotonically from positive to negative values by changing the residual stress in the W nanolayers. Qualitative agreement between experiment and simulation was achieved, confirming a decrease of the interface stress from the compressive to the tensile regime. The DFT simulations showed that Cu atoms at the strained Cu/W interfaces are displaced along the in -plane and out -of -plane directions in response to the interface stress. Using a preliminary neural network potential for the Cu-W system, specific in -plane crystallographic orientation relationships for the Cu/W interfaces were also tested, which improved quantitative agreement between experiment and theory. Assumptions and limitations in experiments and theory for deriving the interface stress are critically discussed.