It has long been postulated that drugs of abuse may represent significant cofactors in the progression of human immunodeficiency virus (HIV)-induced disease. Both HIV infection and drugs of abuse have significant effect on the immune system as well as on the nervous system. In HIV infection, abnormalities in these systems intersect to lead to a constellation of symptoms known as neuroAIDS. Drugs of abuse may synergize with such damage, acting on immune and/or neural cells. However, definitive epidemiological evidence for such an interaction is lacking. Here we review such studies as well as the use of the nonhuman primate/simian immunodeficiency virus system to investigate the interaction of neuroAIDS with drugs of abuse. Furthermore, recent findings on mechanisms of actions of selected drugs reveal the possibility of protective as well as detrimental effects on the central nervous system damage induced by HIV.