Treatment with combination antiretroviral therapy (cART) regimens with a high capacity to penetrate the blood-brain barrier has been associated with lower levels of human immunodeficiency virus (HIV) in the central nervous system (CNS). This study examined neurocognitive performance among a sample of 118 HIV+ substance-dependent individuals (SDIs) and 310 HIV- SDIs. HIV+ participants were prescribed cART regimens with varying capacity to penetrate the CNS as indexed by the revised CNS Penetration Effectiveness (CPE) scale. Participants completed the Rotary Pursuit Task (RPT) and the Weather Prediction Task (WPT)-two measures of procedural learning (PL) with known sensitivity to HIV infection-and a control task of sustained attention. HIV+ SDIs prescribed cART with relatively high CNS penetrance performed significantly more poorly on both tasks than HIV- controls. Task performance of HIV+ SDIs prescribed cART with relatively low CNS penetrance did not differ significantly from either HIV- controls or the HIV+/high CPE group, although a trend toward lower RPT performance than that of HIV- participants was observed. Between-group differences were not seen on a control task of motor impulsivity (Immediate Memory Task), indicating that the observed deficits among HIV+/high CPE SDIs may have some specificity.