Objective: To assess anastomotic leak (AL) risk factors in a large patient series. Design: Case-control study. Setting: The Mount Sinai Hospital. Patients: Ninety patients with AL following colorectal resection and 180 patients who underwent uncomplicated procedures. Main Outcome Measures: Risk factors associated with development of AL. Results: The AL rate was 2.6%. Five risk factors for AL were identified: (1) preoperative albumin level lower than 3.5 g/dL (odds ratio [OR] 2.8; 95% confidence interval [CI], 1.3-5.1) (P=.03); (2) operative time of 200 minutes or longer (OR, 3.4; 95% CI, 2.0-5.8) (P=.01); (3) intraoperative blood loss of 200 mL or more (OR, 3.1; 95% CI, 1.9-5.3) (P=.01); (4) intraoperative transfusion requirement (OR, 2.3; 95% CI, 1.2-4.5) (P=.02); and (5) histologic specimen margin involvement in disease process in patients with inflammatory bowel disease (IBD) (OR, 2.9; 95% CI, 1.4-6.1) (P=.01). Patients with all 3 intraoperative risk factors had an OR of 22.1; 95% CI, 2.8-175.4 (P < .001) for development of AL. Conclusions: Histologic resection margin involvement in disease process in patients with IBD, preoperative albumin levels lower than 3.5 g/dL, intraoperative blood loss of 200 mL or more, operative time of 200 minutes or more, and/or intraoperative transfusion requirement increased AL risk. Enteral nutritional optimization prior to elective surgery is essential. Proximal diversion should be considered for patients with all 3 intraoperative risk factors because they are at high risk for AL.