A puff-by-puff mainstream smoke procedure has been developed that provides the sensitivity and selectivity of a gas chromatography-mass spectrometry (GC-MS) system. The smoke analysis is based on automated sample collection and injection into the GC system. This development builds on, and complements, prior puff-by-puff procedures developed by Philip Morris USA, that utilized infrared (IR) analysis of gas-phase mainstream smoke. IR analysis of the gas-phase smoke for individual smoke constituents relies on the unique spectroscopic absorption patterns of each analyte. The new multiplex procedure relies on both chromatographic separation as well as spectroscopic separation. A significant feature of this method is that multiple injections are made prior to the complete elution of the first injected sample. The benefits of this methodology are that both sensitivity and the number of detected compounds are enhanced. While the multiplex method increases the complexity of the chromatographic data, the mass spectral analysis provides a means for data reduction to meaningful results. Many smoke constituents that are at concentrations below the Fourier transform infrared (FTIR) detection limit are observable with the multiplex analysis while maintaining the feature of puff-by-puff characterization of fresh smoke. The gas-phase mainstream smoke filtration performance of standard adsorption materials are discussed as a demonstration of the versatility and information content of this analytical procedure.