Anastomotic leak (AL) is one of the most serious complications after gastrointestinal surgery. All patients aged 16 years or older who underwent a surgery with single intestinal anastomosis at Morristown Medical Center from January 2006 to June 2008 were entered into a prospective database. To compare the rate of AL, patients were divided into the following surgery-related groups: 1) stapled versus hand-sewn, 2) small bowel versus large bowel, 3) right versus left colon, 4) emergent versus elective, 5) laparoscopic versus converted (laparoscopic to open) versus open, 6) inflammatory bowel disease versus non inflammatory bowel disease, and 7) diverticulitis versus nondiverticulitis. We also looked for surgical site infection, estimated intraoperative blood loss, blood transfusion, comorbidities, preoperative chemotherapy, radiation, and anticoagulation treatment. The overall rate of AL was 3.8 per cent. Mortality rate was higher among patients with ALs (13.3%) versus patients with no AL (1.7%). Open surgery had greater risk of AL than laparoscopic operations. Surgical site infection and intraoperative blood transfusions were also associated with significantly higher rates of AL. Operations involving the left colon had greater risk of AL when compared with those of the right colon, sigmoid, and rectum. Prior chemotherapy, anticoagulation, and intraoperative blood loss all increased the AL rates. In conclusion, we identified several significant risk factors for ALs. This knowledge should help us better understand and prevent this serious complication, which has significant morbidity and mortality rates.