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Background: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is related to the pathophysiology of treatment-resistant depression (TRD). But whether the Val66Met polymorphism is associated with the clinical manifestations of TRD (such as treatment refractoriness and melancholic and anxious distress features) remains unclear. Methods: Totally, 106 patients with TRD were genotyped for the BDNF Val66Met polymorphism. We used the 17-item Hamilton Depression Rating Scale evaluate depressive symptoms (melancholic and anxious distress features) and Maudsley Staging Method to measure treatment refractoriness. Logistic regression models were constructed to study the relationships among the Val66Met polymorphism, melancholic or anxious distress features, and treatment refractoriness. Results: The risk of Val/Met heterozygosity was associated with significantly greater melancholic features than that of Val/Val homozygosity (odds ratio [95% confidence interval (CI)] = (4.67 [1.16–14.24], p < 0.05). The melancholic feature in Val/Met heterozygosity was significantly higher to have the risk in treatment refractoriness than that of Val/Val homozygosity odd ratio (95% CI) = (6.42 [1.70–24.25], p < 0.05). Conclusion: Patients with TRD carrying the BDNF Val/Met genotype are more likely to present with melancholic feature, which is in turn related to high treatment refractoriness.