Mediastinitis is a serious complication after coronary artery bypass grafting (CABG). We studied the risk factors for the development of postoperative mediastinitis in a large group of patients who underwent isolated CABG at Catharina Hospital, Eindhoven, The Netherlands. Data of all patients undergoing an isolated CABG between January 1998 and December 2008 were analyzed. Univariate and multivariate logistic regression analyses were performed to investigate the effect of biomedical variables on the development of mediastinitis. Multivariate analyses were used to test for the confounding effect of various risk factors on outcomes. Mediastinitis was present in 100 out of the 11,748 patients. Preoperative atrial fibrillation [odds ratio = 4.26 (2.26 to 8.02)] and an elevated preoperative C-reactive protein level [odds ratio = 1.013 (1.007 to 1.020)] were important independent predictors of the development of mediastinitis. Other significant risk factors were the following: age, chronic obstructive pulmonary disease, diabetes, morbid obesity, use of extracorporeal circulation, use of bilateral internal mammary arteries, reexploration for ischemia, and perioperative myocardial infarction. Apart from previously described risk factors for the development of postoperative mediastinitis, we found preoperative atrial fibrillation and an elevated C-reactive protein level to be significant predictors of mediastinitis in patients undergoing CABG.