Background: Substance users’ quality of life (QoL) is influenced by several variables, including psychiatric comorbidity and addiction severity. Thus far, the impact of the type of dependence (alcohol, drug or dual dependence) remains unclear. Therefore, the objectives of the study were to evaluate QoL in a clinical sample of alcohol-, drug- and dual-dependent patients and to assess the independent impact of psychiatric comorbidity, addiction severity and type of dependence on QoL. Methods: Face-to-face interviews with 274 patients admitted to residential substance abuse treatment were conducted using the European Addiction Severity Index (EuropASI), the Mini-International Neuropsychiatric Interview and the Assessment of Personality Disorders self-report questionnaire. Results: Multivariate analyses showed that anxiety, mood or personality disorder, employment status and the severity rating on the EuropASI domain alcohol use were associated with overall QoL. Gender, anxiety disorder and the severity ratings on the EuropASI domains alcohol use, drug use, physical health and emotional and psychological health were associated with overall perception of health. Conclusion: Addiction severity and psychiatric comorbidity explained the greatest amount of QoL variance, whereas the type of dependence did not play a central role.