Nelfinavir (NFV) is a currently available HIV-1 protease (PR) inhibitor. Patients in whom NFV treatment has failed predominantly carry D30N mutants of HIV-1 PRs if they have been infected with the subtype B virus. In contrast, N88S mutants of HIV-1 PRs predominantly emerge in patients in whom NFV treatment has failed and who carry the CRF01_AE virus. Both D30N and N88S confer resistance against NFV. However, it remains unclear why the nonactive site mutation N88S confers resistance against NFV. In this study, we examined the resistance mechanism through computational simulations. The simulations suggested that despite the nonactive site mutation, N88S causes NFV resistance by reducing interactions between PR and NFV. We also investigated why the emergence rates of D30N and N88S differ between subtype B and CRF01_AE HIV-1. The simulations suggested that polymorphisms of CRF01_AE PR are involved in the emergence rate of the drug-resistant mutants.