Background and Aim Major Depressive Disorder (MDD) is the most common mental health condition, with a severe decline in performance, disability, and a 15% risk of suicide. Allopurinol increases the level of tryptophan in the body by inhibiting xanthine oxidase, and by elevating the level of tryptophan, i. e., a precursor to serotonin. Accordingly, it can improve the symptoms of depression. This study aimed to investigate the impact of allopurinol on MDD. Methods & Materials In this double-blind clinical trial, 70 patients with MDD, diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Third Edition (DSM IV-TR) were randomly (paired & individual patient records) divided into two equal groups. Both research groups received 40 mg of citalopram daily for 6 weeks. In addition to citalopram, the intervention group received 300 mg allopurinol daily and the control group received a placebo. At the end of the third and sixth weeks, the examined patients were tested for Hamilton Depression Rating Scale (HDRS). Ethical Considerations This study was approved by the Ethics Committee of the Arak University of Medical Sciences (Code: IR. ARAKMU. REC. 1394. 68). Also, it was approved by the Iranian Registry of Clinical Trials (Code: IRCT201508277373n6). Results The Mean± SD HDRS’ s score, after 3 weeks of treatment, in the control and allopurinol groups was measured as 28. 42± 3. 1 and 23. 02± 3. 4, respectively. After 6 weeks after treatment, the Mean± SD depression score in the control and allopurinol groups was equal to 23. 28± 4. 1 and 20. 4± 1. 2, in sequence. A significant difference was observed between the research groups; thus, the intervention group obtained a lower mean score in the HDRS than the controls. Conclusion Allopurinol can improve the symptoms of depression and can also be used as an adjunct in the treatment of depression.