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This cross-sectional study was carried out in two Spanish prisons. A group of 177 HIV-infected prison inmates were interviewed. Standardized personal interviews using a structured questionnaire were conducted to assess sociodemographic features and prison setting characteristics, clinical variables, social support and drug consumption. A simplified four-item questionnaire for self-reported adherence was used. A total of 24.3% were non-adherent. Predictors of non-adherence in the multivariate analysis included poor or lack of ability to follow the prescribed treatment regimen, no visits in a month, anxious and/or depressed mood, difficulty in taking medication, receiving methadone treatment, cannabis consumption and robbery as the reason for imprisonment. Adherence to antiretroviral therapy was higher than in the wider community. However, other variables related to the correctional setting, such as assignments within the facility, adaptability of the prison system to authorize the cell being opened in the event of missed medication, or legal situation had no effect on adherence for inmates with HIV disease.