The aim of this study is to analyse the influence of ply drop-off regions and related parameters on the VARTM cure-induced residual stress generation and related distortions within thick thermoset composites. These parameters include the resin pocket material properties and geometry, ply orientations and cure cycle parameters. By means of a coupled thermal-mechanical cure model it is observed that during the initial part of the cure process, both the chemical shrinkage and thermal expansion of the resin pocket evolve in counteracting manner. The resin pocket geometry and orientation of the surrounding plies influence the out-of-plane direct tensile stress within these plies whenever either the aspect ratio of the resin pocket or the in-plane stiffness of these plies is increased. The orientation of the terminated ply proved to be of influence as well, where higher in-plane shrinkage and thermal contraction of this ply increases the out-of-plane stress around the drop-off region. Implementing multiple drop-off regions introduce stress interactions caused by the different ply orientations used. These regions influence the local out-of-plane stress levels around the drop-off regions, where the stagger distance between these drop-offs generally lowers this effect. As result of this study, existing drop-off design guidelines are reconsidered and new guidelines are proposed for implementing ply drop-off regions within composite laminates.