A gas chromatograph/time-of-flight (GCT) mass spectrometer, with high mass measurement accuracy to within 5 ppm, has been used for the automated accurate mass analysis of multicomponent mixtures and drug discovery compounds. A multicomponent mixture was analyzed several times over the course of a week to assess the reproducibility and ruggedness of the automated method while operating the GCT in electron ionization mode. For example, the data for 31 radical cations generated via electron ionization was processed using automated software (i.e. OpenLynx™) to provide for mass accuracies less than 5 ppm for nearly 100% of the ions from multiple injection data. Mass accuracies of the radical anions of polyaromatic hydrocarbons generated via negative chemical ionization, and protonated pyridines and quinolines generated via methane chemical ionization, were mainly less than 5 ppm from multiple injection data. In addition, the automated method has been used for the accurate mass analysis of drug discovery compounds. Copyright © 2005 John Wiley & Sons, Ltd.