The stress state and intermixing in epitaxial Ni/Mo multilayers grown on (11 2 0) sapphire substrates are investigated using X-ray Diffraction (XRD). Two deposition techniques were used, namely ion beam sputtering (IBS) and magnetron sputtering (MS), to vary the energy of the deposited species. In both cases, high-quality superlattices with a Nishiyama-Wasserman epitaxial relationship Ni  (111) // Mo  (110) were obtained. The residual stress state appears rather complex, resulting from two contributions: a growth-stress whose magnitude and sign depend on growth conditions and coherency stresses of opposite signs in the two elemental sublayers (tensile for Ni and compressive for Mo). Post-growth ion irradiation at low fluences was used to induce structural changes in a controlled way. For the case of IBS, it resulted in partial stress relaxation, as the growth stress could be almost fully relaxed, while the coherency stresses remained unchanged. For the case of MS, a distinct behavior was found: a stress increase of the tensile component of Mo-sublayers was observed, while a stress reduction of the compressive component was noticed. We attribute this phenomenon to ion irradiation induced intermixing. For the Ni sublayers, this intermixing leads to a stress relaxation. The modeling of the stress evolution during ion irradiation was performed using a triaxial stress analysis which enabled us to determine the ‘stress-free and defect-free lattice parameter’, solely linked to chemical effect.