Smokers are exposed to more than 6000 (toxic) smoke components including volatile organic compounds (VOCs). In this study VOCs levels in headspace of blood and exhaled breath, in the mainstream smoke of three types of cigarettes of one brand varying in declared tar, nicotine and carbon monoxide (TNCO) yields are investigated. The objective was to identify whether VOC levels correlate with TNCO yields of cigarettes smoked according to ISO 3308. Our data show that smoking regular and low-TNCO cigarettes result in comparable levels of VOCs in blood and exhaled breath. Hence, declared TNCO-yields as determined with the ISO 3308 machine smoking protocol are irrelevant for predicting VOC exposure upon human smoking. Venous blood and exhaled breath were sampled from 12 male volunteers directly before and 10 min after smoking cigarettes on 3 d (day 1 Marlboro Red (regular), day 2 Marlboro Prime (highly ventilated, low-TNCO), day 3 Marlboro Prime with blocked filter ventilation (taped)). Upon smoking, the levels of toluene, ethylbenzene, m/p-xylene, o-xylene, and 2,5-dimethylfuran in both headspace of venous blood and exhaled breath increase within the same range for all three cigarette types smoked. However, no strong correlation was found between VOC levels in exhaled breath and VOC levels in headspace of blood because of variations between the individual smoking volunteers. More research is required in order to use exhaled breath sampling as a non-invasive quantitative marker for volatile toxicants from cigarette smoke exposure of different brands.