Background Depression is one of the most common mental health disorders, which affiliated more than four percent of world population. Several antidepressant agents, including citalopram were developed. High dose and long-term treatment with these agents along with their side effects decrease the treatment adherence. Using supplements such as acid folic is a way to increase these drug’s efficacy. The aim of this study was to assess the effect of acid folic supplement and increase in blood folate level of the intensity of depression symptoms.Methods This was a randomized-controlled clinical trial. Twenty-four patients with major depression were randomly assigned to two groups. Both groups received citalopram as their standard treatment. The intervention group received acid folic supplement (1mg/daily). The folate levels of blood, Beck's depression inventory and Hamilton depression scale scores were measured. The measurements were conducted before intervention, and in 45 and 90 days follow ups. Data were analyzed using Mann-Whitney U and Friedman tests.Results The blood level of folate was increased for the intervention group. The Hamilton depression scale and Beck Depression Inventory Scores were reduced significantly in both groups after 90 days follow up. There were no significant differences between two groups in the reduction of depression scores. In the intervention group, the decrease of Hamilton's depression scale score was negatively correlated to the increase of blood folate level.Conclusions The increase in blood folate level may be correlate with the decrease in depression symptoms. The use of 1mg/d supplement of acid folic was not effective in the reduction of depression symptoms in patients with major depression.Registered in Iranian Registry of Clinical Trials (IRCT20180115038373N1)