Background: major depressive disorder is one of the most common medical disorders worldwide, having huge impact on physical and mental health in the society and is considered an extended life-threatening psychiatric disorder. Abnormalities in the neurohypophyseal system, neuroendocrine, and immune systems have been reported in depression. Aim of the Work: this study was carried out to identify the relationship between plasma oxytocin level and the severity of major depressive disorder. Patients and Methods: this case control observational study was started from July 2016 till March 2018. The subjects were selected from inpatient and outpatient clinics of Institute of Psychiatry, Faculty of medicine, Ain Shams University. Twenty two female patients were enrolled and fourteen female healthy subjects were considered as controls. Both groups were subjected to Arabic version of Structured Clinical Interview for DSM-IV-TR Axis I Disorders and sampling of serum Oxytocin. Moreover the female patients were subjected to Hamilton rating scale for depression and state trait anxiety inventory to assess the presence of anxiety symptoms. Results: our study revealed reduced serum oxytocin levels in depressed female patients with cutoff point ≤25.6 denoting that below this level shows probability for major depressive disorder in females. Conclusion: our study revealed reduced serum oxytocin levels in depressed female patients. Consistently with the hypothesis of dysregulated OXT biology may serve as a biomarker for major depression.