BACKGROUND: Perioperative blood transfusion in pancreatic cancer patients has been linked to decreased survival; however, a causal mechanism has not been determined. During the processing and storage of packed erythrocytes, biologically active molecules accumulated in the acellular plasma fraction; therefore, the authors hypothesized that the plasma fraction of stored packed erythrocytes promoted tumor progression. METHODS: Proliferation and migration of murine pancreatic cancer and control cells were determined in vitro in response to the plasma fraction from leukocyte and nonleukocyte-reduced fresh versus stored packed erythrocytes. Last, an immunocompetent murine model was used to assess the effect of the plasma fraction of stored and processed packed erythrocytes on pancreatic cancer progression. RESULTS: Incubation of pancreatic cancer cells with the plasma fraction of packed erythrocytes increased proliferation and migration. Intravenous delivery of the acellular plasma fraction to mice with pancreatic cancer significantly increased the tumor weight in both leukocyte-reduced and nonleukocyte-reduced packed-erythrocyte groups (P < .01), although tumor growth and morbidity were greatest in the nonleukocyte-reduced group. CONCLUSIONS: The plasma fraction of stored packed erythrocytes promoted murine pancreatic cancer proliferation and migration in vitro and when administered intravenously, significantly augmented pancreatic cancer growth in immunocompetent mice. © 2010 American Cancer Society.