Objectives: This study was conducted to test the hypothesis that cigarettes that heat rather than burn tobacco reduce exposure to potentially harmful smoke constituents. The levels of biomarkers of exposure (BoExp) to selected potentially harmful cigarette smoke constituents were measured in smokers of conventional lit-end cigarettes (CC), smokers who switched to a prototype test cigarette (TC) that heats rather than burns tobacco, and smokers who stopped smoking (SC) for 5 days. Methods: This was a controlled, randomized, open label, 3 arm parallel group, single centre confinement study conducted in Poland (NCT # 00812279) and performed according to GCP principles. A total of 112 Caucasian smokers of both genders with acceptable health conditions, aged between 23 and 55 years, with a daily consumption of 10 30 cc for at least the last 5 consecutive years, were enrolled. Smokers smoked cc for 2 days (baseline) and were subsequently randomised to one of the study arms: continuing to smoke cc, switching to TC, or switching to smoking cessation (SC) for 5 consecutive days. Except for the SC arm, smoking was allowed ad libitum. The primary objective was to demonstrate a reduction in exposure to carbon monoxide (measured by per cent carboxyhemoglobin [%COHB] in blood), benzene (measured by excretion of s-phenylmercapturic acid [S-PMA] in urine), and NNK (measured by excretion of 4-(methylnitroamino)-1-(3-pyridyl)-1-butanol and glucuronide conjugates [total NNAL] in urine). Additional selected smoke constituents were evaluated. CYP1A2 enzyme activity and safety parameters were also assessed. Results: %COHB, S PMA, and total NNAL were significantly reduced.