Background: Cigarette smoke (CS) is causally linked to the development of cardiovascular diseases (CVD). Tobacco harm reduction, by virtue of 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 occurring and producing substantially lower levels of toxicants than CS. Aims: Our assessment program aims to demonstrate that switching to THS has the potential to reduce the risk of smoking-related diseases compared with continued smoking. Methods: The program includes in vitro/in vivo toxicology testing methods that follow OECD guidelines and Good Laboratory Practice, a systems toxicology approach, and randomized, controlled clinical studies that follow the principles of Good Clinical Practice. Results: The results of the THS assessment program demonstrated that cardiovascular toxicants are reduced by an average of >92% in THS aerosol relative to 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 vivo. Biomarkers linked to the development of smoking-related diseases were analyzed following a 6-month randomized, controlled clinical study with THS, which demonstrated a consistent improvement of biomarkers in different pathophysiologic pathways leading to atherosclerosis. Conclusions: 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 our THS assessment program with cardiovascular outcome studies intended to further support the clinical benefits of switching to THS over continuous smoking.