Abstract Finding the ultimate HIV cure remain a challenging tasks for decades. Various active compounds have been tested against various components of the virus in the effort to halt the virus development in infected host. The idea of finding cure from known pharmacologically active natural occurring compounds is intriguing and practical. Ganoderma lucidum (Ling-Zhi or Reishi) is one of the most productive and pharmacologically active compounds found in Asian countries. It has been used traditionally for many years throughout different cultures. More than a decade ago, el-Mekkawy and co-workers (1998) have tested several active compounds found in this plant. They have successfully identified several active compounds with reasonable inhibitory activity against HIV protease however; no further studies were done on these compounds. This study aimed to elucidate interactions for one of the active compounds of Ganoderma lucidum namely ganoderic acid with HIV-1 protease using molecular docking simulation. This study revealed four hydrogen bonds formed between model34 of ganoderic acid B and 1HVR. Hydrogen bonds in 1HVR-Model34 complex were formed through ILE50, ILE50', ASP29 and ASP30 residues. Interestingly similar interactions were also observed in the native ligand in 1HVR. Furthermore, interactions involving ILE50 and ILE50' residues have been previously identified to play central roles in HIV-1 protease-ligand interactions.These observed interactions not only suggested HIV-1 protease in general is a suitable target for ganoderic acid B, they also indicated a huge potential for HIV drug discovery based on this compound.