BACKGROUND The risk factors for anastomotic leak (AL) after anterior resection have been evaluated in several studies and remain controversial as the findings are often inconsistent or inconclusive. OBJECTIVE To analyze the risk factors for AL after anterior resection in patients with rectal cancer. METHODS Retrospective analysis. METHODS The Nationwide Inpatient Sample 2006 to 2009. METHODS A total of 72 055 patients with rectal cancer who underwent elective anterior resection. METHODS To build a predictive model for AL using demographic characteristics and preadmission comorbidities, the lasso algorithm for logistic regression was used to select variables most predictive of AL. RESULTS The AL rate was 13.68%. The AL group had higher mortality vs the non-AL group (1.78% vs 0.74%). Hospital length of stay and cost were significantly higher in the AL group. Laparoscopic and open resections with a diverting stoma had a higher incidence of AL than those without a stoma (15.97% vs 13.25%). Multivariate analysis revealed that weight loss and malnutrition, fluid and electrolyte disorders, male sex, and stoma placement were associated with a higher risk of AL. The use of laparoscopy was associated with a lower risk of AL. Postoperative ileus, wound infection, respiratory/renal failure, urinary tract infection, pneumonia, deep vein thrombosis, and myocardial infarction were independently associated with AL. CONCLUSIONS Anastomotic leak after anterior resection increased mortality rates and health care costs. Weight loss and malnutrition, fluid and electrolyte disorders, male sex, and stoma placement independently increased the risk of leak. Laparoscopy independently decreased the risk of leak. Further studies are needed to delineate the significance of these findings.