The application of soft photo-ionization mass spectrometry methods (PIMS) for cigarette mainstream smoke (MSS) analysis is demonstrated. Resonance-enhanced multi-photon ionization (REMPI) and vacuum ultra violet light single-photon ionization (SPI) were used in combination with time-of-flight mass spectrometry (TOFMS) for puff-by-puff resolved measurements of tobacco smoke. An optimized smoking machine with reduced memory effects of smoke components was constructed, which in combination with the REMPI/SPI-TOFMS instrument allows PIMS smoke analysis with a time resolution of up to 10 Hz. The complementary character of both PIMS methods is demonstrated. SPI allows the detection of various aliphatic and aromatic components in smoke up to about 120 m/z while REMPI is well suited for aromatic compounds. The capability of the instrument coupled to the novel sampling system for puff-by-puff resolved measurements is demonstrated. Two main patterns of puff-by-puff behaviours are observed for different smoke constituents. The first group exhibits a constant increase in smoke constituent yield from the first to the last puff. The second group shows a high yield of the constituent in the first puff, with lower and constant or slowly increasing amounts in the following puffs. A third group can not be clearly classified and is a combination of both observed profiles. The results also illustrate that the specified quartz fibre filter (Cambridge filter) used for the separation of the smoke particulate matter from the vapour phase causes memory effects due to desorption of deposited material. This effect strongly influences succeeding puffs which must be considered for puff-by-puff resolved interpretation of the gas phase. The feasibility of using the experimental system for intra puff smoke measurements is also shown.