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Strict adherence to antiretroviral treatment (ART) is needed to ensure the effectiveness of HIV treatment. The adverse effects of substance abuse and neurocognitive impairment on medication adherence have both been suggested by several studies. Therefore, the aim of this research is to study the relationship among adherence to ART, cognitive dysfunction, and abuse of certain substances (alcohol, heroin, cocaine, other stimulants, cannabis and benzodiazepines) and/or methadone treatment in our social environment. We performed an observational case-control study with a sample of 125 HIV+ patients, who were classified as patients with poor adherence (cases) and subjects with adequate compliance (controls). Adherence was defined by the Hospital Pharmacy and verified with the Simplified Medication Adherence Questionnaire (SMAQ) and the reference physician's clinical impression. Cognitive functioning was measured with the Zoo Map Test and Trail Making Test (TMT). Substance abuse was collected through a semi-structured clinical interview protocol. Statistical analysis was made using a binary logistic regression model. The results indicate that both alcohol abuse and neurocognitive impairment measured by Zoo Map Test were significantly associated with poorer adherence to ART. No significant association was found between adherence and other substance use, or between adherence and TMT score. Screening of cognitive impairment measured by the Zoo Map Test and alcohol abuse may lead to the development of strategies to improve de adherence to ART in HIV+ patients.