Objective: Clinical and biological correlates of resilience in major depressive disorder are scarce. We aimed to investigate the effect of the Val 66 Met polymorphism in the BDNF gene on resilience scores in major depressive disorder patients and evaluate the polymorphism's moderation effect on resilience scores in response to cognitive therapy. Method: A total of 106 major depressive disorder patients were enrolled in this clinical randomized study. The Resilience Scale and the Hamilton Rating Scale for Depression were applied at baseline, post-treatment, and at six months of follow-up. Blood samples were obtained at baseline for molecular analysis. Results: The baseline resilience scores were higher in patients with the Met allele (114.6617.6) than in those with the Val/Val genotype (104.04621.05; p = 0.037). Cognitive therapy treatment increased resilience scores (p p 0.001) and decreased depressive symptoms (p p 0.001). In the mixed-effect model, the Val/Val genotype represented a decrease in resilience scores (t 218 = -1.98; p = 0.048), and the Val 66 Met polymorphism interacted with sex to predict an increase in total resilience scores during cognitive treatment (t 218 = 2.69; p = 0.008). Conclusion:Our results indicate that cognitive therapy intervention could improve resilience in follow-up, considering that gender and genetic susceptibility are predicted by the Val 66 Met polymorphism.