Background: Type 2 diabetes mellitus (T2DM) is commonly associated with depressive symptoms, which af-fect prognosis and quality of life. We investigated the antidepressant effects of n-3 fatty acids (n-3FAs) mono-therapy (without conventional antidepressants) for T2DM patients with mild to moderate depressive symp-toms. Methods: A 10-wk, placebo-controlled, double-blind, parallel-group (1: 1 ratio) randomized trial of n-3FAs (2700 mg/day EPA: DHA ratio=2) versus placebo in 88 Iranian diabetic patients with mild to moderate de-pression based on Beck Depression Inventory II (BDI-II-PERSIAN) was conducted. This study started from July 2014 to January 2015 in Tehran University of Medical Sciences, Tehran, Iran. The primary event was de-fined as worsened, non-changed, or inconsiderably improved depression (<5 unit decrease in BDI-II-PERSIAN depression scores after treatment) (ClinicalTrials. gov Identifier: NCT02261545). Results: Randomly, 44 T2DM patients were treated with n-3FAs supplements and 44 cases received placebo (three patients discontinued). n-3FAs could significantly protect patients against the aforesaid event and exhibit satisfactory prevention (number needed to treat with 95% confidence interval: 2. 52, 1. 71-4. 74). No serious ad-verse reactions were reported. Conclusion: n-3FAs supplementation had significant antidepressant effects in T2DM patients with mild to moderate depressive symptoms, not confounded by metabolic factors and disease duration.