Smoking is a major risk factor for the development of cardiovascular diseases. Modified risk tobacco products (MRTP) are designed to reduce smoking-related health risks. The present study aimed to evaluate the impact of THS2.2, a candidate heat-notburn technology-based MRTP, compared with a reference cigarette (3R4F), on the adhesion of monocytic cells to human coronary arterial endothelial cells (HCAECs), a critical stage in atherosclerosis development, using a functional in vitro adhesion assay combined with systems toxicology. HCAECs were treated for 4h with conditioned media of human monocytic mono mac 6 (MM6) cells preincubated with low or high concentrations of aqueous extracts from THS2.2 aerosol or 3R4F smoke for 2h (indirect treatment), unconditioned media (direct treatment), or fresh aqueous extract (fresh direct treatment). Previous results showed that aqueous 3R4F smoke extract induced the adhesion of MM6 cells to HCAECs via distinct direct and indirect concentrationdependent mechanisms. Leveraging the same experimental and computational framework, significant reduced effects of aqueous THS2.2 aerosol extract on MM6 cell- CAEC adhesion were measured, also supported by markedly diminished molecular changes such as gene expression in both endothelial and monocytic cells. A shift towards 10 and 20 times higher concentrations of aqueous THS2.2 aerosol extract was required to observe similar effects as the ones measured with 3R4F in both fresh direct and indirect exposure modes, respectively. In conclusion, our in vitro systems toxicology investigations revealed reduced effects ofTHS2.2, a candidate MRTP, on monocytic cell-endothelial cell adhesion compared with a reference cigarette.