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Aim: Alcohol and substance use are the most common comorbidities among patients with schizophrenia, with significantly higher levels of burden reported among primary caregivers. In this study, we aimed to assess the impact of alcohol and substance use on caregivers, and the effects of the severity of disease symptoms and certain attributes of patients and their primary caregivers on the burden, depressive symptoms, quality of life, and anxiety levels of caregivers. Methods: We recruited 100 patients with schizophrenia according to DSM-IV TR from inpatient clinics of Bakirkoy Research and Training Hospital for Psychiatry, Neurology, and Neurosurgery and their primary caregivers from September 2010 to March 2011. The severity of patient symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). All caregivers completed the Sociodemographic and Clinical data form, The Zarit Burden Scale, Beck Depression Inventory, State-Trait Anxiety Inventory, and WHO Quality of life-BREF. Results: The ages of caregivers and patients were 2368 and 2065 years, respectively. The primary caregiver was the patients mother in 53% of cases. We found levels of burden that were significantly higher for caregivers of patients with alcohol or substance use, and these were positively correlated with the positive psychotic subscale of PANSS. Caregivers of patients without alcohol and substance use had significantly higher scores for psychological and social relationship domains of WHOQOL-BREF. Discussion: Alcohol and substance use disorder which causing more complicated and severe needs of schizophrenia patients is associated with increased level of caregiver burden, depression and anxiety levels and decreased quality of life. Our findings suggest that there is a significant relationship between caregiver burden and alcohol and substance use by patients with schizophrenia. [Anadolu Psikiyatri Derg 2017; 18(1.000): 5-12]