The axisymmetric boundary-layer separation of an incompressible impulsively started flow in a wavy-walled tube is analysed at moderate to high values of the Reynolds number. The investigation is carried out by numerical integration of either the Navier–Stokes equations or Prandtl's asymptotic formulation of the boundary-layer problem. The presence of an adverse pressure gradient induces reverse flow at the tube wall independently of the Reynolds number; its occurrence can be predicted by a timescale analysis. Following that, the viscous calculations show different dynamics depending on the Reynolds number. As the Reynolds number increases, the boundary layer has in a well-defined internal structure where longitudinal lengthscales become comparable with the viscous one. Thus the boundary-layer scaling fails locally, with a minimum of pressure inside the boundary layer itself. The formation of the primary recirculation is well captured by the asymptotic model which, however, is not able to describe the roll-up of the vortex structure inside the recirculating region. This inadequacy appears well before the flow evolves to the characteristic terminal singularity usually assumed as foreshadowing the vortex shedding phenomenon. The outcomes are compared with the existing results of analogous problems giving an overall agreement but improving, in some cases, the physical picture.