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Objectives: Conventional biochemical indexes may have predictive values in clinical identification between bipolar disorder (BD) and major depressive disorder (MDD). Methods: This study included 2,470 (BD/MDD = 1,333/1,137) hospitalized patients in Shanghai as training sets and 2,143 (BD/MDD = 955/1,188) in Hangzhou as test sets. A total of 35 clinical biochemical indexes were tested, including blood cells, immuno-inflammatory factors, liver enzymes, glycemic and lipid parameters, and thyroid and gonadal hormones. A stepwise analysis of a multivariable logistic regression was performed to build a predictive model to identify BD and MDD. Results: Most of these biochemical indexes showed significant differences between BD and MDD groups, such as white blood cell (WBC) in the hematopoietic system, uric acid (UA) in immuno-inflammatory factors, direct bilirubin (DBIL) in liver function, lactic dehydrogenase (LDH) in enzymes, and fasting blood glucose (FBG) and low-density lipoprotein (LDL) in glucolipid metabolism (p-values < 0.05). With these predictors for discrimination, we observed the area under the curve (AUC) of the predictive model to distinguish between BD and MDD to be 0.772 among men and 0.793 among women, with the largest AUC of 0.848 in the luteal phase of women. The - 2 values of internal and external validation for male and female datasets were 2.651/10.264 and 10.873/6.822 (p-values < 0.05), respectively. The AUCs of the test sets were 0.696 formales and 0.707 for females. Conclusion: Discrimination and calibration were satisfactory, with fair-to-good diagnostic accuracy and external calibration capability in the final prediction models. Female patients may have a higher differentiability with a conventional biochemical index than male patients. Trial Registration: ICTRP NCT03949218. Registered on 20 November 2018. Retrospectively registered. https://www.clinicaltrials.gov/ct2/show/NCT03949218id= NCT03949218&rank=1. [ABSTRACT FROM AUTHOR]