<br><strong><em>Aims:</em></strong> It is demonstrated that older animals have significantly weaker responses to new alloantigen stimulation than young animals, but the effect on prognosis of perioperative blood transfusion in relation to patient age is unknown. This study is retrospective review to investigate the relationship between perioperative blood transfusion, age at surgery, and clinical outcome in upper gastrointestinal cancer patients. <b><i>Methods:</i></b> We analyzed data of 526 upper gastrointestinal cancer patients who underwent curative resection from 2005 to 2010. <b><i>Results:</i></b> In esophageal cancer patients, patients with blood transfusion experienced significantly shorter overall survival (OS; univariate HR 2.50, p = 0.0006) and disease-free survival (DFS; univariate HR 1.71, p = 0.016) than patients without. Similar results were observed in gastric cancer patients (OS; univariate HR 3.35, p = 0.0001 and DFS; univariate HR = 3.18, p < 0.0001). Furthermore perioperative blood transfusion may be an independent prognostic factor in esophageal cancer patients (multivariate HR = 2.07, p = 0.026). Interestingly, age at surgery significantly affected the influence of blood transfusion on patient outcome in esophageal cancer patients (p for interaction = 0.022). <b><i>Conclusion:</i></b> The negative effect of perioperative blood transfusion was particularly evident among younger patients with esophageal cancer
