1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-thymine(HEPT) and its analogues inhibit HIV-1 reverse transcriptase(RT) selectively. A series of HEPT analogues were analyzed in order to disclose the relationship between their structure and the activity. Thirty-two HIV-IRT inhibitors were investigated by means of comparative molecular field analysis (CoMFA). Based upon the active conformation extracted from the HEPT/HIV-IRT complex, all the inhibitors were aligned and minimized in energy. Three kinds of CoMFA models were established and evaluated. The model( I)of steric and electrostatic effects on their activities showed a higher ability to explain and predict the activities of these selective HIV-1 inhibitors than other models, cross-validated R-CV(2) = 0.870, non-cross-validated R-2 = 0.986, F = 294. 546, standard error (SE) = 0.146. The CoMFA model established by examining the steric and electrostatic effect on the structure without considering the effect of pi value shows a very high ability to predict the biological activity for testing set compounds and training set compounds and offers an approach to design the new inhibitors. The CoMFA model revealed that the suitable length of the 1-side chain is crucial for the antiviral activity. And it also showed that the bulkier group in 5-position and the para-position of the 6-phenylthio group is also benefit for the enhancement of the antiviral activity.