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The correlation between vitamin D deficiency and depression has recently been put forward and resulted in controversial findings. The present study was conducted to find out the effect of 2 single injections of 150,000 and 300,000 IU of vitamin D on improving the depression in depressed patients with vitamin D deficiency.This clinical trial study was carried out during 2011–2012 in Yazd, Islamic Republic of Iran. A total of 120 patients who had a Beck Depression Inventory II score of 17+ and were affected with vitamin D deficiency were randomly assigned to 3 groups of 40. They included G300, G150, and NTG. G300 and G150 received an intramuscular single dose of 300,000 and 150,000 IU of vitamin D, respectively, and the NTG group received nothing. After 3 months of intervention, the depression state, serum vitamin D, calcium, phosphorus, and parathormone were measured.The median of serum vitamin D after intervention were 60.2, 54.6, and 28.2 nmol/L (P < 0.001) for the G300, G150, and NTG, respectively. Percentages of vitamin D deficiency after intervention were 18, 20, and 91.2 for the groups, respectively. The serum calcium mean showed a statistically significant increase in just the 2 test groups receiving vitamin D. There was only significant difference in mean of Beck Depression Inventory II test score between G300 and NTG (P = 0.003).The results of the study revealed that first, the correction of vitamin D deficiency improved the depression state, and second, a single injection dose of 300,000 IU of vitamin D was safe and more effective than a 150,000-IU dose.