Neuroinflammation has been implicated as a major contributor to neuronal injury in HIV-associated neurocognitive disorders (HAND). Previous in vitro and animal studies have shown that drugs of abuse can create a pro-inflammatory environment in the CNS that can potentiate HAND; however, clinical research studies are lacking, especially during the early years of HIV infection when therapeutic intervention would likely make the greatest difference in disease progression. A total of 82 male participants with variable drug use history (no drug use: n=17, occasional drug use: n=25, heavy drug use: n= 40) were enrolled within one year of HIV infection and followed longitudinally. All participants were enrolled when antiretroviral therapy (ART)-naive, and initiated ART during follow up outside of the study. Paired plasma and cerebrospinal fluid (CSF) samples and neuropsychological testing data were collected from participants at baseline, 6 weeks, and every 6 months thereafter for up to four years. Mixed model analyses were conducted to compare the effect of drug use on levels of CSF and plasma neopterin, a marker of macrophage activation, and neuropsychological testing performance. Pre-ART, both plasma and CSF neopterin levels were elevated in the heavy drug use group compared to the no drug use group (plasma: beta = +7.1, SE = 2.4, p = 0.003; CSF: beta = +7.4, SE = 1.9, p <0.001). The difference in neopterin levels was attenuated post-ART in plasma (beta = +3.6, SE = 2.2, p = 0.10), but persisted in CSF (beta = +4.4, SE =1.9, p = .019). Neuropsychological assessment showed that participants with heavy drug use had the greatest impairments both pre- and post- ART (pre-ART heavy vs. none: beta = -0.32, SE = 1.1, p = .006; post-ART heavy vs. none beta = -0.46, SE = 1.2, p <0.001). We conclude that drug use potentiates neuroinflammation in HIV infection and exacerbate neurocognitive impairment in this early HIV infection study.