Display omitted •Non-proportional loading paths imposed on nickel-based superalloy using crystal plasticity.•Potential mechanistic explanation for non-proportional detrimental effects in fatigue proposed.•Non-proportionality giving more slip activations, driving up GND and leading to shorter lives. A dislocation and gradient-based crystal plasticity finite element study of fatigue has been carried out for nickel-based superalloy RR1000 in order to investigate detrimental non-proportional effects on fatigue life. Six differing multiaxial loading cycles including both proportional and non-proportional paths have been addressed and a critical stored energy density criterion employed for fatigue life. Non-proportional paths are shown to lead to higher numbers of intragranular slip system activations, reflecting experimental observations. These give higher geometrically necessary dislocation (GND) densities resulting from slip system interaction occurring through latent hardening effects in the model. The higher GND densities in turn drive up local stress and stored energy densities, thereby leading to lower predicted fatigue lives, in keeping with non-proportional fatigue experiments in the alloy considered. Intragranular slip system interaction may be the mechanistic explanation for non-proportional effects in fatigue of engineering alloys.