© 2015 Elsevier Ltd. Background: Major depressive disorder (MDD) is a widespread psychiatric disorder with incapacitating symptoms. Oxidative stress has been identified to play a role in the pathophysiology of MDD. Objective: To evaluate the therapeutic effectiveness of a chemically defined and antioxidant-rich Chlorella vulgaris extract (CVE) as adjunct to standard treatment in patients suffering from MDD. Methods: Subjects with MDD diagnosis according to DSM-IV criteria who were receiving standard antidepressant therapy were assigned to add-on therapy with CVE (1800. mg/day; n = 42), or continued standard antidepressant therapy alone (n = 50) for a period of 6 weeks. Changes in the frequency of depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory II (BDI-II) scale. Results: There were significant reductions in total and subscale BDI-II and HADS scores in both CVE and control groups by the end of trial. The magnitude of reductions in total BDI-II score [-4.14 (-5.30 to -2.97)] as well as physical [-2.34 (-2.84 to -1.84)] and cognitive [-1.12 (-1.62 to -0.61)] subscales were significantly greater in the CVE versus control group, however, reduction of the affective symptoms was greater in the control compared with the CVE group [0.95 (0.18-0.72)]. Total HADS [-3.71 (-4.44 to -2.98)] as well as individual subscales of depression [-1.46 (-2.02 to -0.90)] and anxiety [-2.25 (-2.74 to -1.76)] were reduced to a greater degree in the CVE group. CVE was well tolerated and no serious adverse event was reported. Conclusion: This pilot exploratory trial provides the first clinical evidence on the efficacy and safety of adjunctive therapy with CVE in improving physical and cognitive symptoms of depression as well as anxiety symptoms in patients who are receiving standard antidepressant therapy.