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Objective: Bile spillage occurs frequently during laparoscopic cholecystectomies, yet its impact on postoperative outcomes remains unknown. We sought to evaluate whether it increases the risk of surgical site infections. Design: Prospective study. Setting: Academic hospital. Patients: Those who underwent laparoscopic (or laparoscopic converted to open) cholecystectomy from 05/2010 to 03/2017. Open cholecystectomies were excluded. Patients were assessed during hospitalization and in the clinic two to four weeks postoperatively. Main Outcome Measure: The rate of surgical site infections in patients with and without bile spillage. Results: Of 1,001 patients, 50% underwent laparoscopic cholecystectomy for acute cholecystitis, 21% for symptomatic cholelithiasis or biliary colic, 13% for gallstone pancreatitis, and 16% for other indications. Bile was spilled in 591 patients (59%) with hydrops noted in 10.5% and empyema in 14.6% of them. In 202 (10.2%) patients bile spillage was accompanied by stone spillage. Patients with bile spillage were older (median age of 52 versus 42, p<0.001) and more likely to be male (44.8% versus 27.8%, p<0.001). Bile spillage occurred more frequently in those undergoing urgent surgery (62.9% versus 48.3%, p<0.001). Furthermore, bile was spilled more frequently with conversion to open (13.3% versus 4.4%, p<0.001). Bile spillage was associated with higher overall postoperative complication rates (25.0% versus 13.6%, p<0.001), surgical site infection rates (7.1% versus 2.4%, p=0.001), and longer hospital stay (median of 3 versus 2 days, p<0.001). In the multivariable analysis, conversion to open (odds ratio=2.96, 95% confidence interval=1.46-5.99) and bile spillage (odds ratio=2.37, 95% confidence interval=1.05-5.37) were independent predictors of surgical site infections. Conclusions: Bile spillage is associated with surgical site infections and surgeons should take extra caution to avoid it during laparoscopic cholecystectomy.