The perceived vibro-acoustic comfort, inside the passenger compartment, under driving conditions, is strictly related to the car body torsional behavior. The aim of this work was to identify which parts of a car body most influence the first torsional mode, in order to modify them and acquire an increase in such car body natural frequency. It was also intended to exploit the great potential of 3D printing that allows an increase in the complexity of component shapes, with an acceptable compromise with respect to production costs. A design and material (from steel to aluminum) change of a car body rear part, which was identified as the structural part of the car body with the most relevant impact on the frequency of the first torsional mode, was assessed in terms of structural and vibro-acoustic performances. In particular, with the constraint of increasing the structural and vibro-acoustic performances and, at the same time, minimize the weight of the structure itself, geometric, structural (e.g., type of connections), and material changes of the car body rear part were assessed. Working on a car model dating back to 2008, which was already compliant with structural and vibro-acoustic regulatory norms, an increase of 2 Hz on the first torsional mode frequency of the Trimmed Body model was obtained. In parallel, a weight reduction in the optimized components was also gained. It was also requested to lower the cabin sound pressure levels, optimizing the vibro-acoustic transfer functions from the accelerations at engine mounts and suspension attachment points to the cabin inside. It was shown how the combined use of advanced topological and structural optimization tools, with the capabilities of an unconventional manufacturing technology, such as 3D printing in aluminum, could guarantee an increase in the vibro-acoustics and structural car performances, also gaining a weight reduction.