Background Delirium is a common, morbid, and costly syndrome that occurs frequently after surgery for atherosclerosis. We hypothesized that vascular risk factors and mildly impaired cognitive performance would independently predispose nondemented patients to develop delirium after noncardiac surgery. Methods The International Study of Postoperative Cognitive Dysfunction recruited patients undergoing noncardiac surgery from 8 countries. Subjects provided detailed medical history and underwent preoperative testing of multiple cognitive domains with a neuropsychologic battery. Postoperatively, subjects (n=1161) were assessed daily for delirium. Results Ninety-nine subjects (8%) developed delirium. In bivariable analysis, several vascular risk factors were significantly associated with the likelihood of delirium, including male sex, exposure to tobacco, previous myocardial infarction, and vascular surgery. After adjustment for age, tobacco exposure and vascular surgery were independent vascular risk factors for delirium (adjusted relative risk [RR] 3.2, 95% confidence interval [CI], 2.1-4.9). In addition, mildly impaired cognitive performance, defined as performance 1.5 standard deviation below the mean on either of 2 neuropsychologic tests, was independently associated with delirium (adjusted RR 2.2, 95% CI, 1.4-3.6). Subjects with both vascular risk factors and mildly impaired cognitive performance were at double the risk of delirium (RR 2.2, 95% CI, 1.2-4.2) compared with those with either of these risk factors alone. Conclusions Vascular risk and mildly impaired cognitive performance independently predispose patients to delirium after noncardiac surgery. These factors will help to identify high-risk patients for delirium and to design and target future intervention strategies.