In order to investigate the quantitative structure-retention relationship in gas chromatography (GC) of mercapto-esters, alcohols, aldehydes, and ketones, the molecular structure RX is divided into two parts, R and X to generate structural parameter. It was proposed that the retention index (RI) is affected by three main factors for mercaptocompounds: alkyl group R, substituted group X, and interaction between R and X. On the basis of the PEI index previously developed by Cao, the novel total polarizability effect index (TPEI) combining with odd-even index (OEI) previously developed in our team, were used to predict the RI of mercapto-compounds. A high quality model (R 2 ¼ 0.9839, s ¼ 23.5, F ¼ 1432.2) was generated using only calculated descriptors and multiple linear regression techniques. Good results were also obtained for the external data set.