OBJECTIVE To identify characteristics associated with mortality and the development of multiorgan dysfunction in patients who had undergone cardiac surgery and required prolonged mechanical ventilation, ie, > 48 h. METHODS A prospective cohort study. METHODS Barnes Hospital, St. Louis, an academic tertiary care center. METHODS A total of 107 consecutive patients undergoing cardiac surgery and requiring prolonged mechanical ventilation. METHODS Prospective patients surveillance and data collection. METHODS ICU mortality and multiorgan dysfunction. RESULTS Among 472 consecutive patients admitted to the cardiac surgery ICU following surgery, 107 (22.7%) required prolonged mechanical ventilation. Twenty-one of these patients (19.6%) died during their hospitalization. In a logistic-regression analysis, the development of an organ system failure index (OSFI) of 3 or greater was the only characteristic independently associated with ICU mortality (p < 0.001). The occurrence of an antibiotic-resistant infection (adjusted odds ratio [AOR] = 6.1, 95% confidence interval [CI] = 2.5 to 14.6 p = 0.006), an aortic cross-clamp time equal to or greater than 1.25 h (AOR = 3.9, CI = 2.3 to 6.8, p = 0.016), the development of ventilator-associated pneumonia (AOR = 3.6, CI = 2.4 to 5.3, p < 0.001), and an APACHE III score equal to or greater than 30 (AOR = 3.1, CI = 1.8 to 5.3, p = 0.036) were independently associated with the development of an OSFI of 3 or greater. CONCLUSIONS These data confirm that acquired multiorgan dysfunction is the best predictor of mortality in patients requiring prolonged mechanical ventilation following cardiac surgery. Additionally, they identify potential determinants of multiorgan dysfunction and suggest possible interventions for its reduction in this patient population.