This randomized, controlled, forced-switching, open-label, parallel-group, single-center study in 90 male and female adult smokers evaluated six biomarkers of tobacco smoke exposure over a 12-week period of unrestricted smoking in the participants’ normal life setting. Baseline biomarker levels were measured, then participants were randomly assigned to switch to an electrically heated cigarette smoking system (EHCSS, Series K) or to continue smoking a conventional cigarette (CC) of similar tar yield (Federal Trade Commission method) for 12 weeks. Compared to Baseline, adult smokers who switched to the EHCSS for 12 weeks in their normal life setting had significantly reduced nicotine equivalents (−33%), total NNAL (a biomarker for NNK, −63%), 1-OHP (a surrogate biomarker for polycyclic aromatic hydrocarbons, −38%), carboxyhemoglobin (a biomarker for carbon monoxide, −23%), 3-HPMA (a biomarker for acrolein, −25%) and S-PMA (a biomarker for benzene, −49%), whereas exposure was stable in the CC control group.