Background: Depressive symptoms are expected consequences following a diagnosis of breast cancer and have a detrimental effect on the prognosis of the disease. Aim: This study aimed to detect the benefits of adding the antidepressant drugs to the usual supportive psychotherapy provided by the oncology team to depressed breast cancer patients. Methods: 400 breast cancer patients were screened for depression to reach the sample size (130) of depressed cancer patients, they were assessed for the presence of depression using SCID-I. Then, 130 depressed patients who had breast cancer were randomly categorized into two groups; Group I (65) received both of antidepressant medication (Mirtazapine) and usual supportive psychotherapy by the oncology team, while the other group; Group II (65) were subjected to the usual supportive psychotherapy alone with three months follow up. Diagnostic and Statistical Manual of Mental Disorders, (DSM-IV, SCID-I): was used to confirm a diagnosis of major depressive disorder. Initial assessment and after three months the two groups were reassessed specifically at the Hospital Anxiety and Depression Scale (HADS), as well as the scale for quality of life (WHOQOL-BREF). Results: Statistically significant difference (p-value = 0.021, 0.032) between studied groups (group I and group II) as regard depression and anxiety domains of HADS respectively ,as well as the (WHOQOL) .Also a statistically significant association was revealed between depression severity and anxiety severity with total mastectomy (p=0.001, p<0.001 respectively). Conclusion: Adding the antidepressant drugs to the usual supportive psychotherapy provided by the oncology team have better improvement of depressed breast cancer patients than using psychotherapy alone, as well as improve their quality of life. Keywords: Depression; Breast Cancer; Mirtazapine; Sharkia