HIV-1 Associated Dementia (HAD) develops during progressive HIV-1 infection and is characterized by cognitive impairments, behavioral disorders and potential progressive motor abnormality. Abnormal inflammation within the central nervous system (CNS), activation of macrophage/microglia and involvement of proinflammatory cytokines have been suggested as primary factors in the pathogenesis of HAD. Impairment of neuronal function and neuronal cell death are believed to be the end pathophysiological result of HAD. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, was suggested to participate in apoptotic cell death during HAD. As a death ligand, TRAIL was originally thought to target only tumor cells. TRAIL is not typically present in CNS; however, emerging data show that TRAIL can be induced by immune stimuli on macrophage and microglia, major disease effector cells during HAD. Upregulated TRAIL may then cause neuronal apoptosis through direct interaction with TRAIL receptors on neurons or through macrophage death-mediated release of neurotoxins. In this review, we summarize the pivotal role of TRAIL in HAD and TRAIL-initiated intracellular death cascades that culminate in neuronal apoptosis as observed in HAD.