Objective To investigate the effect of HIV infection on inosine-5’-monophosphate dehydrogenase 2(IMPDH2) expression in the cerebral temporal cortex. Methods Montreal Cognitive Assessment (MoCA) scores and magnetic resonance imaging were used to assess mild cognitive impairment in HIV-infected patients. In addition, the histologic structure of the temporal cortex in a rhesus macaque with chronic simian-human immunodeficiency virus (SHIV) KU-1 infection was examined using hematoxylin and eosin staining. Moreover, IMPDH2 protein expression levels in paired healthy and infected temporal cortex were examined using immunohistochemistry and Western blot. Finally, putative genes associated with IMPDH2 expression were investigated using protein-protein interaction network analysis. Results HIV positive individuals had a thinner temporal cortex compared with healthy controls. In addition, the numbers of neurons in the temporal cortex were decreased and IMPDH2 protein levels were significantly lower in the infected monkey compared with healthy controls. Eight genes interacting with the IMPDH2 gene were identified. Conclusions Downregulation of IMPDH2 protein in the temporal cortex might be involved in the pathogenesis of HIV-related neurocognitive disease.