Quantitative structure-activity relationships (QSAR) have been established for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase (RT). Of these 87 nonnucleoside RT inhibitors, 9 novel HEPT analogues were used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity model. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the HEPT series. Indeed, the QSAR model provides evidence concerning the conformational transformations the molecules may undergo during the inhibition process. The established relationships are supplementary to the experimental study on the binding of HEPT type inhibitors to RT by Hopkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study suggests a quantitative interpretation of the structure-activity relationships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEPT type RT inhibitors.