ACKGROUND: Many data support that oxidative stress and inflammation represent a pathway to pathology in a number of depressed patients. Therefore, investigating this pathway presents an area for developing potential therapeutic strategies for depression. AIM: This study compares the serum level of malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear factor erythroid 2-related factor 2 (Nrf2) in depressed and non-depressed subjects and correlate between their levels with severity of disorder, socio-demographic characteristics, previous hospitalization, and number of episodes. METHODS: A total of 60 patients diagnosed with major depressive disorder (MDD) from the Psychiatric Outpatient Clinic in Al-Zahra University Hospital, Cairo, Egypt, during the period from July 1, 2018, to December 31, 2018. A cross-matched control group of 60 subjects was selected from employers working in the hospital, complete psychiatric history, Hamilton Depression rating scale was done and serum levels of MDA, Nrf2, and SOD were estimated. RESULTS: No statistical difference between patient and control group was observed regarding age, sex, education, and marital status. The number of patients with mild depression was 28 (46.7%), moderate depression 18 (30%), and severe depression 14 (23.3%). The mean duration of illness in years was 6.13, and mean number of episodes was 3.66. MDA level was significantly elevated in the patient group than the control one. Meanwhile, SOD and Nrf2 were significantly lower in the patient group than the control. There was significant relationship between duration of illness and number of episode