The aim of this study was to elucidate the clinical picture of Major Depressive Disorder (MDD) with polymorphisms involving the IL6 gene. It was a systematic review with a search for original articles in the Scopus, Web of Science, PubMed, and BVS databases, which provided information on genetic variants related to IL6 gene polymorphisms. Studies that did not present complete data, including statistical data, were excluded. Fifty-four articles were found in the databases. The Rayyan platform was used to remove duplicates and read abstracts for initial selection. Twelve articles remained, and those that were freely accessible were selected for full reading, totaling 5 articles for this review. Evidence suggests a systemic condition in MDD, with data demonstrating inflammatory alterations. Given that in most studies, patients with MDD had higher inflammatory states, there appears to be a relationship between IL-6 and the disorder. IL-6 induces changes in the brain, activates microglia, and controls neuronal health, potentially making the relationship between polymorphisms and the disease tangible, but there are still few studies in the field.