Objective: The aim of this study was to analyze the impact of psychiatric comorbidity and severity of dependence on health-related quality of life (HRQoL).Methods: One hundred and ninety-eight substance use disorder (SUD) patients were recruited from an outpatient center that provides treatment for SUD. The International Personality Disorder Examination Screening Questionnaire (IPDE-SQ), Mini International Neuropsychiatric Interview (MINI), Substance Dependence Severity Scale (SDSS) and Health-Related Quality of Life for Drug Abusers test (HRQoLDA test) were administered.Results: Patients with psychiatric comorbidity evaluated their HRQoL more negatively than patients without psychiatric comorbidity. An analysis of the relationship between severity of dependence and HRQoL scores indicated significant correlations among alcohol-, cocaine-, heroin- and cannabis-dependent patients. According to multivariate analyses, anxiety disorders, mood disorders, severity of dependence on alcohol, cannabis, cocaine, paranoid, borderline and avoidant personality disorders (PDs) were observed to have a major impact on HRQoL.Conclusions: SUD (severity of dependence on alcohol, cannabis and cocaine) and other mental disorders (anxiety disorders; mood disorders; paranoid, borderline and avoidant PDs) are involved in the deterioration of the SUD patients' HRQoL. This study demonstrates the need for integrated treatment for SUD patients. Treating only a part of the problem (whether SUD or other mental disorders are present) is insufficient for improving quality of life.