Background: Comorbidity of substance abuse and mental disorders is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration, and higher service utilization. Therefore, identifying key clusters of comorbidity represent important steps toward improving mental health care. Objective: To assess the relationship between opioid addiction and the comorbidity of major depressive disorders, explore the characteristics of patients using different types of opioids, and assessment of the severity of addiction and depression. Patients and Methods: The sample consisted of 229 patients diagnosed with opioid use disorder according to DSM -IV, and their ages ranged from 15-50 years old. They were subjected to a semi-structured interview sheet, a structured clinical interview for DSM-IV (SCID-I) to diagnose psychiatric disorders, the addiction severity index scale, urine drug screening, and Hamilton depression scale. Results: The most common psychiatric comorbidity was major depressive disorder representing 32.8% of the total sample. Patients with comorbid major depressive disorder had statistically significant higher history of suicidal attempt, history of overdose, number of treatment trials, and previous admission for addiction problems as compared with patients with no comorbidity. The prevalence of MDD comorbidity was 55% among tramadol users, 26.2% in heroin users, and 18.8% in Nalbuphine users. Conclusion: There was a significant relation between opioids addiction and major depressive disorder, between the severity of addiction and psychiatric comorbidity.