Human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause significant neurologic disease. Central nervous system (CNS) involvement of HIV has been extensively studied, with well-documented invasion of HIV into the brain in the initial stage of infection, while the acute effects of SARS-CoV-2 in the brain are unclear. Neuropathologic features of active HIV infection in the brain are well characterized whereas neuropathologic findings in acute COVID-19 are largely non-specific. On the other hand, neuropathologic substrates of chronic dysfunction in both infections, as HIV-associated neurocognitive disorders (HAND) and post-COVID conditions (PCC)/long COVID are unknown. Thus far, neuropathologic studies on patients with HAND in the era of combined antiretroviral therapy have been inconclusive, and autopsy studies on patients diagnosed with PCC have yet to be published. Further longitudinal, multidisciplinary studies on patients with HAND and PCC and neuropathologic studies in comparison to controls are warranted to help elucidate the mechanisms of CNS dysfunction in both conditions