Smoking conventional cigarettes (CCs) exposes smokers to harmful and potentially harmful constituents (HPHCs). The Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product, was developed to reduce or eliminate the formation of HPHCs, while preserving as much as possible the taste, sensory experience, nicotine delivery profile and ritual characteristics of CC. This randomized, controlled, open-label study in confinement for 5 days aimed to demonstrate the reduction in exposure to selected HPHCs, to assess nicotine uptake and subjective effects, in subjects switching to THS 2.2 (n = 80) compared to a group continuing smoking CCs (n = 40) and participants abstaining from smoking (n = 40). The subjects were randomized according to sex and daily CC consumption. The levels of biomarkers of exposure to HPHCs were significantly reduced in participants switching to THS 2.2, compared to CC use. More importantly, the magnitude of exposure reduction observed was close to that which was seen in participants who abstained from smoking for 5 days, while nicotine uptake was maintained. Reduction in urge-to-smoke was comparable between THS and CC groups, however THS 2.2 was slightly less satisfactory than CCs. The new, alternative tobacco product THS was well tolerated.