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To investigate the potential additive effects of blood transfusion and sepsis on colon cancer disease-specific survival, cardiovascular disease-specific survival, and overall survival after colon cancer surgery.Perioperative blood transfusions are associated with infectious complications and increased risk of cancer recurrence through systemic inflammatory effects. Furthermore, recent studies have suggested an association among sepsis, subsequent systemic inflammation, and adverse cardiovascular outcomes. However, no study has investigated the association among transfusion, sepsis, and disease-specific survival in postoperative patients.The New York State Cancer Registry and Statewide Planning and Research Cooperative System were queried for stage I to III colon cancer resections from 2004 to 2011. Propensity-adjusted survival analyses assessed the association of perioperative allogeneic blood transfusion, sepsis, and 5-year colon cancer disease-specific survival, cardiovascular disease-specific survival, and overall survival.Among 24,230 patients, 29% received a transfusion and 4% developed sepsis. After risk adjustment, transfusion and sepsis were associated with worse colon cancer disease-specific survival [(+)transfusion: hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.09–1.30; (+)sepsis: HR 1.84, 95% CI 1.44–2.35; (+)transfusion/(+)sepsis: HR 2.27, 95% CI 1.87–2.76], cardiovascular disease-specific survival [(+)transfusion: HR 1.18, 95% CI 1.04–1.33; (+)sepsis: HR 1.63, 95% CI 1.14–2.31; (+)transfusion/(+)sepsis: HR 2.04, 95% CI 1.58–2.63], and overall survival [(+)transfusion: HR 1.21, 95% CI 1.14–1.29; (+)sepsis: HR 1.76, 95% CI 1.48–2.09; (+)transfusion/(+)sepsis: HR 2.36, 95% CI 2.07–2.68] relative to (−)transfusion/(−)sepsis. Additional analyses suggested an additive effect with those who both received a blood transfusion and developed sepsis having even worse survival.Perioperative blood transfusions are associated with shorter survival, independent of sepsis, after colon cancer resection. However, receiving a transfusion and developing sepsis has an additive effect and is associated with even worse survival. Restrictive perioperative transfusion practices are a possible strategy to reduce sepsis rates and improve survival after colon cancer surgery.