Fullerene and its derivatives have potential to be utilized in many biomedical applications. In the present study, we investigated the role of fullerene derivatives as inhibitors of HIV-RT by combined protein-ligand docking approach and QSAR methods. The study shows the best predictive QSAR model that represents a two-variable model. It has a good ratio of the number of descriptors and predictive ability. The main contributions to the inhibitory activity are provided by signal JhetZ descriptor and mu (dipole moment, as a measure of the polarity of a compound). The developed GA-MLRA-based model demonstrates a good performance, confirmed by statistics The structure-activity analysis of these fullerene analogues allowed us to design and suggest for synthesis a set of new potentially active fullerenes. Finally, the molecular docking analysis was carried out to understand the details of interactions between HIV-RT and fullerene-C-60 derivatives.