Cocaine use increases the neurotoxic severity of human immunodeficiency virus-1 () infection and the development of HIV-associated neurocognitive disorders (). Among the studied cellular mechanisms promoting neurotoxicity in HIV-1 and cocaine use, central nervous system () immunity, such as neuroimmune signaling and reduced antiviral activity, are risk determinants; however, concrete evidence remains elusive. In the present study, we tested the hypothesis that cocaine self-administration by transgenic HIV-1 () rats promotes CNS inflammation. To test this hypothesis, we measured cytokine, chemokine, and growth factor protein levels in the frontal cortex (f) and caudal striatum (c). Our results demonstrated that cocaine self-administration significantly increased fCTX inflammation in HIV-1 rats, but not in the cSTR. Accordingly, we postulate that cocaine synergizes with HIV-1 proteins to increase neuroinflammation in a region-selective manner, including the fCTX. Given the fCTX role in cognition, this interaction may contribute to the hyperimmunity and reduced antiviral activity associated with cocaine-mediated enhancement of HAND.