Aim: Anastomotic leakage (AL) is a major challenge in colorectal cancer surgery due to increased morbidity and mortality. Possible risk factors should be investigated differentially, distinguishing between rectal and colonic surgery in large-scale studies to avoid selection bias and confounding. Method: The incidence and risk factors associated with AL were analysed in an unselected nation-wide prospective cohort of patient subjected to curative colonic cancer surgery with primary anastomosis and entered into The Danish Colorectal Cancer Group database between May 2001 and December 2008. Results: AL occurred in 593 (6.4%) of 9333 patients. Laparoscopic surgery (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.05-1.70; P = 0.03); left hemicolectomy (OR, 2.02; 95% CI, 1.50-2.72) or sigmoid colectomy (OR, 1.69; 95% CI, 1.32-2.17; P = 0.01); intraoperative blood loss (OR, 1.04; 95% CI, 1.01-1.07; P = 0.03); blood transfusion (OR, 10.27; 95% CI, 6.82-15.45); P <0.001) and female gender (OR, 0.71; 95% CI, 0.57-0.89; P = 0.02) were associated with AL in the multivariate analysis. Conclusion: The main finding that a laparoscopic approach was associated with increased risk of AL should prompt close future monitoring. There was no evidence that centralization of surgery to high volume hospitals reduced the rate of AL. © 2012 The Authors Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.