Anastomotic leakage in colorectal surgery remains a major challenge because of its early and late consequences. To determine whether prevalence and risk factors for anastomotic leakage (AL) differed between right and left elective colectomy for cancer, we conducted univariate and multivariate analyses and compared 33 variables (15 preoperative, 18 intraoperative) culled prospectively for 520 right and 1,230 left colectomies, followed by immediate anastomosis in 1,750 adult patients with or without AL. The overall AL rate was 4% (71 of 1,750) and was significantly lower (p < 0.0001) for right (7 of 520=1.35%) than for left colectomy (64 of 1,230=5.20%). Overall mortality was 4.1% (68 of 1,750), and was not statistically different (p=0.50) between right (4.6%, 24 of 520) and left (3.6%, 44 of 1,230)) colectomy. In right colectomy, differences in associated mortality rates with (14.3%, 1 of 7) and without (4.5%, 23 of 513) AL were not statistically significant (p=0.28), but in left colectomy, associated mortality was statistically significantly higher (p < 0.006) with AL (10.9%, 7 of 64) than without it (3.2%, 37 of 1,166). Independent risk factors for AL were preoperative in right colectomy: loss of weight (> 10%), odds ratio (OR)=5.62, with 95% CI 1.06 to 29.8; and intraoperative in left colectomy: palliative resection (OR=2.12; 95% CI 1.06 to 4.23), "poor" colonic cleanliness (OR=2.4; 95% CI 1.34 to 4.28), proximal colorectal anastomosis (OR=1.34; 95% CI 1 to 1.8), and distal colorectal anastomosis (OR=3.91; 95% CI 1.64 to 9.81). In right colectomy for cancer, preoperative nutritive support leading to regain of lost weight could reduce postoperative morbidity. Concerning left colectomy, if colonic cleanliness is poor, intraoperative colonic lavage should be done. When poor colonic cleanliness is associated with palliative resection and low distal rectal anastomosis, a protective stoma should be considered.