The Tobacco Heating System 2.2 menthol (mTHS) was developed to reduce or eliminate the formation of harmful and potentially harmful smoke constituents (HPHCs) in the aerosol through heating and not burning tobacco, while preserving as much as possible taste, sensory experience, nicotine delivery profile and ritual characteristics of menthol cigarettes(mCC). The study reported is part of a global clinical program for THS and was designed to demonstrate sustained exposure reduction to selected HPHCs in smokers pre –dominantly using mTHS and to provide first insight on changes in clinical risk endpoints(CRE)when switching from mCC to mTHS use for 5 days in confinement followed by an ambulatory period of 85 days, compared to subjects continuing to smoke mCC and those who abstained from smoking.Biomarkers of exposure (BoExp) to 16 HPHCs were assessed to provide an assessment of human uptake of a variety of representative toxicants contained in combustible tobacco products. Selected CREs associated with cardiovascular, respiratory disease and genotoxicity as well as subjective effects to investigate the acceptance of mTHS compared to mCC were also assessed in this study.