Background:Major depressive disorder is a condition associated with dysregulated cytokine levels; among these, IL6. Furthermore, genetic variations within cytokine genes have been proposed to predict antidepressant treatment outcome. Objectives:This study aims to evaluate the role ofIL6-174G > CandIL6R D358A A > Cfunctional polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse, and treatment resistant depression (TRD). Methods:The referred polymorphisms were genotyped in 80 MDD patients followed at Hospital Magalhães Lemos, Portugal, within a period of 27 months. Results:It was found that patients carryingIL6-174GC genotype present a protection towards the development of TRD (OR = 0.242; 95% CI = 0.068–0.869;p = .038), when compared with GG genotype. Additionally, carriers ofIL6-174 CC genotype remit earlier than patients withIL6-174GG/GC genotypes, with a median time to remission of 6 weeks for CC carriers and 15 weeks for GG or GC carriers (p = .030, Log-rank test). No association was found betweenIL6RD358A genetic polymorphism and any of the treatment phenotypes evaluated. Conclusions:TheIL6-174G > Cpolymorphism influences antidepressant treatment outcome in this sub-set of MDD patients, providing a putative mechanistic link for the dysregulated IL-6 levels described in the literature in patients with TRD. [ABSTRACT FROM AUTHOR]