Background: Previous studies have documented that blood transfusion incites a substantial inflammatory response with the systemic release of cytokines. Furthermore, blood transfusion is a significant independent predictor of multiple organ failure in trauma. The objective of this study was to assess the risk of systemic inflammatory response syndrome (SIRS) and intensive care unit (ICU) admission, length of stay (LOS), and mortality in trauma patients who require blood transfusion. Methods: Prospective data were collected on 9,539 trauma patients admitted to the R. Adams Cowley Shock Trauma Center over a 30-month period from January, 1997 to July, 1999. Complete SIRS data were available on 7,602 patients. Patients were stratified by age, gender, race, Glasgow coma scale (GCS), and injury severity score (ISS). A systemic inflammatory response to a wide variety of severe clinical insults (SIRS) was defined as a SIRS score of ≥2, as calculated on admission. Blood transfusion was assessed as an independent predictor of SIRS, ICU admission and length of stay, and mortality. Results: The mean age of the study cohort was 37 ± 17 years; the mean ISS was 9 ± 9 points. Seventy-one percent of the patients were male, and 85% sustained blunt trauma. Blood transfusion within the first 24 h was administered to 954 patients, comprising 10% of the study cohort. Transfused patients were significantly older (43 ± 20 vs. 36 ± 16 years, p < 0.00001), had higher ISS (22 ± 12 vs. 8 ± 7 points, p < 0.00001), and lower GCS (12 ± 4 vs. 14 ± 2 points, p < 0.00001) than non-transfused patients. Blood transfusion and increased total volume of blood transfusion was associated with SIRS. Blood transfusion was also a significant independent predictor of SIRS, ICU admission, and mortality in trauma patients by multinomial logistic regression analysis. Trauma patients who received blood transfusion had a two- to nearly sixfold increase in SIRS (p < 0.0001) and more than a fourfold increase in ICU admission (OR 4.62, 95% CI 3.84-5.55, p < 0.0001) and mortality (OR 4.23, 95% CI 3.07-5.84, p < 0.0001) compared to those that were not transfused. Linear regression analysis revealed that transfusion was an independent predictor of ICU LOS (Coef. 5.20, SE 0.43, p < 0.0001). Transfused patients had significantly longer ICU LOS (16.8 ± 14.9 vs. 9.9 ± 10.6 days, p < 0.00001) and hospital LOS (14.5 ± 15.5 vs. 2.5 ± 5.3 days, p < 0.00001) compared to non-transfused patients. Conclusions: Blood transfusion within the first 24 h was an independent predictor of mortality, SIRS, ICU admission, and ICU LOS in trauma patients. The use of blood substitutes and alternative agents to increase serum hemoglobin concentration in the post-injury period warrants further investigation.