Objectives This study sought to evaluate the impact of postoperative delirium with/without cerebral ischemia on short- and long-term mortality in a large cohort of cardiac surgery patients. Design The study constituted a prospective cohort observation of patients following various cardiac surgery procedures. Setting The investigation was conducted in a single high-volume tertiary cardiac surgery center. Participants Consecutive candidates for cardiac surgery (n = 8,792) from 2003 to 2008 were subjected to the following exclusion criteria: History of any psychiatric disorders, alcohol abuse and intake of psychoactive drugs and incomplete data. Interventions No additional interventions were performed, except for standard perioperative management. Measurements and Main Results 5,781 patients finally were assigned to cohorts depending on the presence of postoperative delirium with/without cerebral ischemia and then prospectively followed up over the median time of 46 months. Overall 30-day mortality in patients with delirium was 15.25%, including 6.43% of patients without and 38.46% of subjects with cerebral ischemia. After adjustment for more than 100 perioperative variables, short-term mortality was associated independently with delirium (OR = 3.735), stroke (OR = 5.698), hypertension (OR = 0.333), urgency of surgery (OR = 13.018), baseline plasma glucose and protein concentrations and blood transfusions (AUROC for the model 0.94). Long-term mortality in patients who developed delirium was 23.31%, including 15.2% of patients without and 44.62% of those with postoperative stroke. Long-term mortality independently corresponded with stroke (HR = 3.968), urgent surgery (HR = 27.643), baseline plasma glucose and protein concentrations, chronic obstructive pulmonary disease and blood transfusions. Impact of postoperative delirium was insignificant (p = 0.2). Compared to subjects with cerebral ischemia, death in patients only with delirium was less frequently of cardiovascular cause (p < 0.01). Conclusions Delirium with/without cerebral ischemia significantly worsened the short-term prognosis. Stroke, yet not delirium, considerably increased the long-term mortality, especially of cardiovascular origin.