HIV integrase has emerged as a promising target for discovery of agents against the acquired immunodeficiency syndrome (AIDS) pandemic. With the purpose of designing new chemotypes with enhanced potencies against the HIV integrase enzyme, the QSAR study carried out on 37 novel phthalimide derivatives is presented. The developed QSAR model was validated by standard statistical parameters and through a detailed structural study of how it reproduces and explains the quantitative differences seen in experimentally known pharmacological data. The model showed a good correlative and predictive ability having a cross-validated correlation coefficient (r2cv) of 0.709 and a conventional correlation coefficient (r2) of 0.949. The predictive correlation coefficient (r2pred) was found to be 0.512. The study revealed that the antiretroviral activity is predominantly explained by the substituent size, shape and polarity and provided insights into how modulation of the steric bulkiness and polarities of the substituents could be made to optimize the integrase-inhibitor interaction chemistry. A detailed investigation was made of the structural basis for the antiretroviral activity and the findings from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.