A Quantitative Structure-Activity Relationship (QSAR) study has been carried out using topological indices, physicochemical and indicator parameters on a series of HEPT analogues for their HIV reverse transcriptase inhibitory activity. Correlation analysis and multiple linear regression (MLR) method were used to find out the best QSAR model. The results clearly explained that decreased hydrophobicity of substituents at R(1) and R(2) positions are favorable for the activity and presence of di-substitution at phenyl ring as well as i-Pr at R(1) position have detrimental effect but presence of OH group at R(2) position increases the activity. The atoms numbered as 1, 2, 3, 4, 5, 6 and 11 may constitute pharmacophore moiety of the HEPT analogues for their anti-HIV activity. Leave one out (LOO-) cross validation method was used to judge the predictive power of final equations. From the study one can propose that atom or fragmental level descriptors are more useful to interpret drug-receptor interactions in these analogues. The potentiality of ETSA index to recognize these atoms (Pharmacophoric atoms) was established.