Background: Leukocyte-depleted packed red blood cells (PRBC) were introduced to reduce potential immunomodulatory effects and transfusion- associated morbidity. It has, however, remained unclear, if leucocyte depletion prevents negative side effects of blood transfusion. The aim of this analysis was to examine the effects of leukocyte-depleted PRBC on surgical morbidity after elective colon cancer surgery. Methods: Data were prospectively collected from 531 consecutive patients undergoing elective colon cancer surgery at a single high-volume center (University Hospital) from 2002 to 2008. Potentially predictive factors for surgical morbidity were tested on univariate and multivariate analysis. Results: A total of 531 patients with colon cancer were included. A curative (R0) resection was performed in 497 patients (94%). The mortality rate, overall morbidity rate, and surgical morbidity rate were 1.1, 33, and 21%, respectively. Some 135 patients (25%) received perioperative transfusion of PRBCs. On multivariate analysis age (odds ratio [OR] 1.04, 95% confidence interval [95% CI] 1.02-1.06; P = 0.001), BMI (OR 1.08, 95% CI 1.03-1.13; P = 0.003), and PRBC transfusion (2.4, 1.41-4.11; P = 0.001) were revealed as independent predictors of surgical morbidity. The risk of surgical complications increased continuously with the amount of transfused PRBCs. The adverse impact of PRBC transfusion was neither restricted to the timepoint of transfusion (intraoperative or postoperative), nor to the kind of complication (infectious vs noninfectious complication). Conclusion: Perioperative transfusion of leukocyte-depleted PRBCs has a significantly negative effect on surgical morbidity of patients undergoing elective colon cancer surgery. The use of perioperative blood transfusions in these patients should be avoided, whenever possible.