OBJECTIVES: This study aimed to investigate the role of estrogen in the differential diagnosis of depression and schizophrenia and its relationship with the curative effects, adverse events. METHODS: From 2017 to 2019, patients with depression or schizophrenia treated with modern electroconvulsive therapy (MECT) were studied retrospectively. Their serum estrogen levels, Hamilton Depression Scale, and Brief Psychiatric Rating Scale scores were collected. Differences in the estrogen levels between patients with depression and schizophrenia before and after treatment and the correlation of the estrogen level with curative effect and adverse events was evaluated. In total, 67 patients with depression and 61 with schizophrenia were included. RESULTS: There were no significant differences in the baseline characteristics, except the estrogen level (p < 0.001). Serum estrogen levels increased in both groups after MECT (117 vs. 141 pmol/L, p < 0.001; 42 vs. 46 pmol/L, respectively; p < 0.001), and higher estrogen levels were positively correlated with better outcomes (p < 0.001). CONCLUSION: Post-MECT estrogen levels were not associated with the incidence rate of adverse events of MECT. Estrogen plays a promising role in distinguishing depression and schizophrenia and evaluating the therapeutic efficacy of MECT.