HIV-1 protease is a key enzyme for viral maturation because it cleaves precursor polypeptides into mature structural and functional proteins. The introduction of protease inhibitors into therapy in the mid-1990s has dramatically changed the AIDS panorama worldwide. However, resistance to currently available protease inhibitors remains a serious challenge that must be overcome. Herein, we report a fragment-based QSAR study of a series of highly potent HIV-1 protease inhibitors, as well as the structural basis of their binding affinity. Hologram QSAR (HQSAR) analyses were performed, resulting in robust statistical models that consistently correlated the bioactivity profile with the two dimensional molecular descriptors. The robustness of the best model was assessed based on the correlation coefficients (q(2) = 0.70 and r(2) = 0.90), as well as the prediction of the activity of an external test set (r(2) pred = 0.75). Structure-based molecular modeling studies were performed to investigate the binding mode of the best inhibitor in the active site of the enzyme. The HQSAR model and the structural findings provide valuable insights for the rational design of structurally related HIV-1 protease inhibitors.