This study is part of a clinical program to assess the Tobacco Heating System 2.2 (THS 2.2), a candidate modified risk tobacco product. The objective of this study was to assess the maximum potential reduction in exposure to selected harmful and potentially harmful constituents (HPHCs) after 5 days of use of THS 2.2 under controlled conditions compared to continued smoking of combustible cigarettes (CC) and smoking abstinence (SA). Biomarker of exposure (BoExp) to fourteen HPHCs were evaluated. This was an open-label, randomized, controlled, 3-arm parallel group, confinement study in 160 healthy smokers aged between 21 and 65 years. Smokers smoked their CC at baseline for 2 days, and were subsequently randomized to continue to smoke CC, to switch to THS 2.2, or to stop smoking for 5 days. Twenty-four hour urine was collected to evaluate the levels of BoExp using validated methods. This study was conducted according to GCP and is registered in ClinicalTrials.gov, number NCT01959932. At the end of exposure, the levels of all evaluable BoExp were significantly reduced by at least 50% in the THS 2.2 arm as compared to CC and approaching results obtained in the SA arm. The reductions in BoExp levels were observed within 24 hours of starting THS 2.2 use. The average daily product use between baseline and the end of exposure slightly increased in the THS 2.2 arm, and remained in the same range in the CC arm. The Nicotine Equivalents were similar in both arms throughout the exposure period. THS 2.2 was well tolerated.THS 2.2 showed a significant reduction in exposure to HPHCs after 5 days of THS 2.2 use, as compared to CC, approaching levels of HPHCs observed after 5 days of smoking abstinence.