Acquired immune deficiency syndrome (ALDS) is caused by the human immunodeficiency virus (HIV) type 1 and 2 (HIV-1 and HIV-2). HIV-1 is observed worldwide while HIV-2 though prevalent in West Africa is persistently spreading to other parts of the world. An important target for AIDS treatment is the use of HIV protease (PR) inhibitors preventing the replication of the virus. In this work, the popular molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the effectiveness of the HIV-1 PR inhibitors darunavir, GRL-06579A, and GRL-98065 against HIV-2 and HIV-1 protease. The affinity of the inhibitors for both HIV-1 and HIV-2 PR decreases in the order GRL-06579A > darunavir > GRL-98065, in accordance with experimental data. On the other hand, our results show that all these inhibitors bind less strongly to HIV-2 than to HIV-1 protease, again in agreement with experimental findings. The decrease in binding affinity for HIV-2 relative to HIV-1 PR is found to arise from an increase in the energetic penalty from the desolvation of polar groups (DRV) or a decrease in the size of the electrostatic interactions between the inhibitor and the PR (GRL-06579A and GRL-98065). For GRL-98065, also a decrease in the magnitude of the van der Waals interactions contributes to the reduction in binding affinity. A detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of efficient inhibitors against HIV-2 protease.