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Although highly active antiretroviral therapy (HAART) has improved survival rates of HIV patients, HIV-associated neurocognitive disorders (HAND) still exist in a highly prevalent group of persons with this disease. In this study we seek to evaluate the influence of drug use in the neuropsychological performance of seropositive drug users. We carried out an extensive neuropsychological evaluation and compared the performance of seropositive drug users (n=90) with that of a control group of seronegative drug users (n=48). The results reveal that methadone maintenance programmes can make the seropositive subject neuropsychologically vulnerable. Likewise, we found that giving up drugs have a protective effect in the presence of neuropsychological alterations associated with HIV. These findings lead us to suggest that seropositivity is not sufficient to explain the neuropsychological alterations of seropositive drug users, noting that these alterations are multifactorial.