Numerical simulations of column collapse and pyroclastic density current (PDC) scenarios at Vesuvius were carried out using a transient 3D flow model based on multiphase transport laws. The model describes the dynamics of the collapse as well as the effects of the 3D topography of the volcano on PDC propagation. Source conditions refer to a medium-scale sub-Plinian event and consider a pressure-balanced jet. Simulation results provide new insights into the complex dynamics of these phenomena. In particular: 1) column collapse can be characterized by different regimes, from incipient collapse to partial or nearly total collapse, thus confirming the possibility of a transitional field of behaviour of the column characterized by the contemporaneous and/or intermittent occurrence of ash fallout and PDCs; 2) the collapse regime can be characterized by its fraction of eruptive mass reaching the ground and generating PDCs; 3) within the range of the investigated source conditions, the propagation and hazard potential of PDCs appear to be directly correlated with the flow-rate of the mass collapsing to the ground, rather than to the collapse height of the column (this finding is in contrast with predictions based on the energy-line concept, which simply correlates the PDC runout and kinetic energy with the collapse height of the column); 4) first-order values of hazard variables associated with PDCs (i.e., dynamic pressure, temperature, airborne ash concentration) can be derived from simulation results, thereby providing initial estimates for the quantification of damage scenarios; 5) for scenarios assuming a location of the central vent coinciding with that of the present Gran Cono, Mount Somma significantly influences the propagation of PDCs, largely reducing their propagation in the northern sector, and diverting mass toward the west and southeast, accentuating runouts and hazard variables for these sectors; 6) the 2D modelling approximation can force an artificial radial propagation of the PDCs since it ignores azimuthal flows produced by real topographies that therefore need to be simulated in fully 3D conditions.