Polycyclic aromatic hydrocarbons (PAHs), tobacco-specific nitrosamines (TSNAs) and aromatic amines are carcinogens present in cigarette smoke. These compounds are distributed in the human body and they could be transferred to the foetus during the pregnancy. Placenta is the main barrier to these toxic compounds and its study is the objective of this work. A method based on solid-phase extraction (SPE) with ultra-performance liquid chromatography−tandem quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) has been examined and optimized for the analysis of 9 target analytes (4 tobacco-specific nitrosamines and some of their metabolites, 3 aromatic amines, nicotine and cotinine) in 26 placenta samples from smoking and non-smoking women. Limits of detection (LODs) were in the range of 3–27 ng/g of placenta. Nicotine, cotinine, N-nitrosoanatabine (NAT) and 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK) metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were detected in the placenta samples of smoking woman. Nicotine was detected in 3 out of 8 placentas from smoking women, always below the limit of quantification (88 ng/g). This could be expected, as the half-life of nicotine in the body is limited to about 0.5–3 h. Cotinine, the main metabolite from nicotine, was detected in all placentas from smoking women at concentrations between 17.2 and 61.8 ng/g, reaching the highest values for those women that smoked the highest number of cigarettes. NAT and NNAL were detected in all placentas from smoking women, always below the limit of quantification (40 ng/g and 33 ng/g respectively).