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Lobna A Saleh,1– 3 Farooq M Almutairi,2,4 Wejdan K Alorabi,1 Bashayr A Alkuhayli,1 Shaden S Alzaidi,1 Shahad B Alzahrani,1 Futun A Aljumayi,1 Maram H Abduljabbar,1 Ayidh S Alharthi,1 Mashhour A Alsufyani,1 Mohammed H Alhazmi,1 Abdulbari A Althobaiti,1 Fahad N Almutairi,1 Fahad S Alshehri,5 Ebtehal Altowairqi,1 Yusuf S Althobaiti1,2,6 1Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 2Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Taif, Saudi Arabia; 3Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, University of Hafar Al-Batin, Hafar Al-Batin, Saudi Arabia; 5Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 6General Administration for Precursors and Laboratories, General Directorate of Narcotics Control, Ministry of Interior, Riyadh, Saudi ArabiaCorrespondence: Yusuf S AlthobaitiDepartment of Pharmacology and Toxicology, College of Pharmacy, Taif University, Health Science Campus, P.O. Box 11099, Airport Road, Al Haweiah, Taif, 21944, Saudi ArabiaTel +966 545736200Email ys.althobaiti@tu.edu.saPurpose: Depression is one of the most common psychological disorders. The nutritional etiology of the depression proposes that vitamin D may play a significant role in the pathogenesis of depression. Further, vitamin D deficiency has been found to aggravate depression in animals. Therefore, vitamin D treatment might be a potential therapeutic aid in depression management. This study aimed to explore the antidepressant effects of vitamin D in a Bacillus Calmette-Guerin (BCG)-induced depression model.Methods: Thirty-six mice were randomly assigned to short-term and long-term experimental groups. In each group, mice were randomly subcategorized into three subgroups: 1. control (received vehicle), 2. BCG (received BCG [107 CFU/mouse]), and 3. BCG + vitamin D (received vitamin D [60.000 IU/kg] before BCG [107 CFU/mouse] inoculation). After completion of the two experimental periods (3 days for the short-term group and 2 weeks for the long-term group), the mice underwent three behavioral tests: locomotor activity, the forced swimming test (FST), and the tail suspension test (TST).Results: Locomotor activity did not significantly differ among the subgroups in either the long-term or short-term groups. In the short-term group, the total immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. However, in the TST, no significant difference was found between the vitamin D-treated group and the BCG group. In the long-term group, the immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. Similarly, the total immobility time on the TST was also significantly lower in the vitamin D-treated mice than in the BCG-treated mice.Conclusion: Vitamin D is useful in the management of depressive behavior. The potential role of vitamin D in the etiology of depression should be investigated in future work.Keywords: depression, natural supplements, tail suspension test, forced swimming test