Although our understanding of how human immunodeficiency virus (HIV)-related neurobehavioural deficits develop is nascent and preliminary, some clues have emerged which may clarify lingering uncertainties. In particular, HIV seems to yield brain dysfunction by mediating pathological changes upon neuronal function. HIV also compromises immunological integrity, thereby resulting in secondary infections that may further increase brain dysfunction. Notably, many individuals with HIV tend to be current or past abusers of drugs, and, in some cases, their drug use may have actually presented a pathway for initial HIV infection. Similar to HIV, many drugs tend to yield pathological changes upon neuronal function. Further paralleling HIV, some drugs seem to compromise immune function, which in turn may yield secondary detrimental effects upon the brain. Yet, despite the relatively high comorbidity rates of HIV infection and substance abuse, few investigations have addressed the potential interaction between these two factors upon neurobehavioural status. Towards this end, the present paper reviews the existing literature concerning neuropsychological effects of HIV and substance use, and suggests potential mechanisms whereby substance use may potentiate and exacerbate the onset and severity of neurobehavioural abnormalities in HIV infection.