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Background: Major depressive disorder (MDD) and bipolar disorder (BPD) are two of the most important mental disorders that greatly impact different aspects of life. These conditions imply heavy health and economic burden and are heterogeneous in nature. Inflammation is reported as the etiology of mental disorders. Nrf2 transcription factor plays a key role in the defense mechanisms against inflammation and oxidative stress. So, this study aimed to evaluate the expression level of Nrf2 in MDD and BPD patients and compared it with healthy control subjects. Materials and Methods: In this study, real-time PCR was conducted to evaluate the expression level of Nrf2 in 100 MDD and 100 BPD patients compared to 100 healthy control subjects. Statistical analysis conducted on GraphPad Prism 8 and SPSS21 included ANOVA, Tukey’s test, receiver operating characteristic (ROC), and odds ratio. Results: Results suggest a significant downregulation of Nrf2 in these conditions compared to the control group. ROC curve analysis demonstrates Nrf2 as a biomarker of these psychiatric disorders. Conclusion: The elevated levels of reactive oxygen species and downregulation of detoxifying enzymes were observed in MDD and BPD, which can be associated with the downregulation of Nrf2. Concerning its role in inflammatory response pathways, alternation of Nrf2 expression can be associated with the pathology of these conditions.