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 evaluate the pharmacokinetic (PK) profile of nicotine following single use of THS 2.2 menthol as compared to combustible cigarettes (CC) and nicotine nasal spray (NNS). This was, an open-label, randomized, two-period, four-sequence crossover study conducted in 62 healthy smokers. Each period consisted of 2 days, with 1 day of smoking abstinence (nicotine wash-out), and 1 day of single use of THS 2.2 Menthol, CC or NNS with every subject being exposed to 2 of the 3 study products (THS 2.2 Menthol/CC and THS 2.2 Menthol/NNS). During the single use day, a total of 16 venous blood samples were collected including 1 sample prior to product use and at various time points up to 24 hours. PK parameters were calculated using a non-compartmental model. Urge-to-smoke was assessed using the Questionnaire of Smoking Urges-brief (QSU-b). This study was registered with ClinicalTrials.gov, number NCT01967719. For THS 2.2 menthol, the values for AUC(0-last) and Cmax were lower compared to CC in the THS 2.2 Menthol/CC group. In the THS 2.2 Menthol/NNS group, AUC(0-last) and Cmax were higher for THS 2.2 Menthol compared to NNS. The tmax was longer for CC than for THS 2.2 Menthol in the THS 2.2 Menthol/CC group and the tmax for NNS was longer compared to the tmax for THS 2.2 Menthol in the THS 2.2 Menthol/NNS group. A reduction from baseline in QSU-b score was observed 15-30 minutes after single use for both, THS 2.2 Menthol and CC, greater than the reduction after 45-60 minutes following NNS. THS 2.2 Menthol was well tolerated. The differences observed in PK parameters (Cmax, AUC(0-last) and tmax) for THS 2.2 Menthol compared to CC and NNS, can best be explained due to differences in product use behavior. A transient reduction in urge-to-smoke was observed with THS 2.2 menthol, slightly lower compared to CC but higher than NNS after single use.