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Regional anesthesia may play a beneficial role in long-term oncological outcomes. Specifically, it has been suggested that it can prolong recurrence-free survival and overall survival after gastrointestinal cancer surgery, including gastric and esophageal cancer, by modulating the immune and inflammatory response. However, the results from human studies are conflicting. The goal of this systematic review was to summarize the evidence on the impact of regional anesthesia on immunomodulation and cancer recurrence after gastric and esophageal surgery. We conducted a literature search of 5 different databases. Two independent reviewers analyzed the quality of the selected manuscripts according to prespecified inclusion and exclusion criteria. Randomized controlled trials were assessed for potential sources of bias by using the Cochrane Risk of Bias tool. A total of 6 studies were included in the quality analysis and systematic review. A meta-analysis was not conducted for several reasons, including high heterogeneity among studies, low quality of the reports, and lack of standardized outcomes definitions. Although the literature suggests that regional anesthesia has some modulatory effects on the inflammatory and immunological response in the studied patient population, our systematic review indicates that there is no evidence to support or refute the use of epidural anesthesia or analgesia with the goal of reducing cancer recurrence after gastroesophageal cancer surgery.