Ion mobility spectrometry (IMS) analysis of a complex mixture of volatile organic compounds (VOCs) and organophosphorus compounds (OPCs) at vapor levels of 10–40 mg/m3 produced mobility spectra with broad profiles illustrating limitations of ion mobility spectrometry (IMS) for screening such mixtures. Preseparation of this mixture with a gas Chromatograph inlet to an ion mobility spectrometer enhanced analytical selectivity although OPC detection was complicated by co-elution with other VOCs. Water reagent gas in the ion source of the ion mobility spectrometer yielded 46 gas Chromatographic peaks in a mixture of 45 VOCs and 19 OPCs. Co-elution of two materials was observed in eight of the Chromatographic peaks and co-elution of three materials occurred in four instances. Further selectivity was gained using reagent gases of elevated proton affinity in the ion source. Reagent gas chemistry for acetone and dimethylsulfoxide reduced the number of GC peaks to 26 and 20, respectively. Moreover, spectral integrity and quantitative response for OPCs were retained at 50 to 1000 pg levels with these reagent gases. For OPCs, analyte ions were shown to be of the type M2H+ under these conditions of analysis and the mobilities of the product ions were independent of reagent gas. Reduced mobility values were assigned to OPC spectra using a well-characterized OPC ion as the reference. Spectral profiles and reduced mobilities suggested that the OPC product ions were not clustered with reagent gas molecules at 100 °C.