Rationale Monitoring of isomeric analytes using mass spectrometry usually requires a time‐consuming chromatographic separation of the analytes before analysis. Selected ion flow tube mass spectrometry (SIFT‐MS) can provide rapid direct analysis of ethylbenzene and xylene by utilizing the different reaction chemistry of the isomers. O 2 + yields the same product ions from each isomer but in different ratios. OH − yields different product ions. Methods The reaction chemistry of C 8 H 10 with the reagent ion OH − generated from a microwave discharge of moist air in a commercial SIFT‐MS instrument was utilized in this study. The product ion from OH − yielded ions at different masses for each isomer. To gain an understanding of how the product ion from ethylbenzene of HO 2 − was generated, a theoretical study of the potential reaction surface was undertaken that accounted for the experimental observations. Results Measurements of OH − with ethylbenzene showed the product ion to be HO 2 − at m/z 33. The reaction of OH − with xylene yielded the major product ion at m/z 105, C 8 H 9 − . HO 2 − also underwent a slow secondary reaction with CO 2 and O 2 present from air in the samples. These findings were supported by calculations of the potential energy surface for the reactions. Measurements made on a certified gas mixture of ethylbenzene and xylene in the concentration range up to 5000 ppbv gave a linear response for each analyte. Conclusions A fast, efficient method was developed for monitoring xylene and ethylbenzene in a mixture without the need for chromatographic separation before analysis using SIFT‐MS.