Introduction: Cigarette smoke (CS) is causally linked to the development of cardiovascular disease (CVD) through different pathophysiologic pathways, which include endothelial injury and dysfunction, oxidative stress, a procoagulatory status, inflammation, and an abnormal lipid profile, all factors contributing to the development of atherosclerosis. Tobacco harm reduction, by substituting cigarettes with less harmful products, is a complementary approach to current strategies for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS) 2.2 is a novel tobacco product that heats tobacco instead of burning it, never allowing the temperature to exceed 350°C, thereby preventing the combustion process from taking place and producing substantially lower levels of toxicants compared with CS. Method: Our assessment program aims to demonstrate that switching to THS has the potential to reduce the risk of smoking-related diseases versus continued smoking. The program includes in vitro/in vivo toxicology testing methods that follow OECD guidelines, Good Laboratory Practice, and a systems toxicology approach as well as a randomized, controlled clinical studies following the principles of Good Clinical Practice. Results: The results of the THS translational assessment program demonstrated that cardiovascular toxicants are reduced by more than 92% in THS aerosol versus CS and that THS aerosol contains no solid carbon-based nanoparticles. The effects of THS aerosol on the adhesion of monocytic cells to human coronary endothelial cells in vitro are significantly reduced. Switching to THS halted the progression of CS-induced atherosclerotic changes in ApoE-/- mice in in vivo studies. Clinical risk endpoints (CRE) linked to the development of smoking-related diseases were analyzed following a six-month randomized, controlled clinical study with THS that demonstrated a consistent improvement of CREs in different pathophysiologic pathways leading to atherosclerosis. Conclusion: The evidence available to date indicates that switching to THS has the potential to reduce the risk of smoking-related diseases, such as CVD. As a next step, we will complement the THS assessment program with health outcome studies intended to further support the clinical benefits of switching to THS as compared with continuous smoking.