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This study was to investigate the characteristics of seasonal symptoms and non-enzymatic oxidative stress in the first hospitalized patients with bipolar and unipolar depression, aiming to differentiate bipolar depression from unipolar depression and reduce their misdiagnosis. A total of 450 patients with bipolar depression and 855 patients with depression were included in the present study. According to the season when the patients were admitted to the hospital due to the acute onset of depression, they were further divided into spring, summer, autumn and winter groups. According to the characteristics of symptoms of bipolar disorder in the DSM-5, the characteristic symptoms of bipolar disorder were collected from the medical record information, and clinical biochemical indicators that can reflect the oxidative stress were also recorded. The seasonal risk factors in patients with bipolar or unipolar depression were analyzed. The relationship of age and gender with the bipolar or unipolar depression which attacked in winter was explored. There were significant differences between groups in the melancholic features, atypical features and conjugated bilirubin in spring. In summer, there were significant differences between groups in the melancholic features, uric acid and conjugated bilirubin. In autumn, there were marked differences between groups in melancholic features, anxiety and pain, atypical features, uric acid, total bilirubin, conjugated bilirubin and albumin. In winter, the conjugated bilirubin and prealbumin were significantly different between two groups. The melancholic features and uric acid that in summer as well as melancholic features, uric acid and total bilirubin in autumn were the seasonal independent risk factors for the unipolar depression as compared to bipolar depression. In winter, significant difference was noted in the age between two groups. In conclusion, compared with patients with unipolar depression, patients with bipolar depression have seasonal characteristics. Clinical symptoms and indicators of oxidative stress may become factors for the differentiation of seasonal unipolar depression from bipolar depression. Young subjects aged 15–35 years are more likely to develop bipolar depression in winter.