The purpose of this prospective, quantitative, comparative study, conducted at the 55 bed cardiothoracic intensive care unit of the Heart Institute (InCor), University of Sao Paulo Medical School, was to identify factors involved in the weaning of patients who require long-term (> 10 days) mechanical ventilation after cardiac surgery. The subjects included all patients who underwent open-heart surgery with cardiopulmonary bypass during a 10 month period from April 2000 to January 2001 (n = 946). From this group, 52 (5.7%) patients who required a tracheotomy for the management of long-term mechanical ventilation after cardiac surgery with cardiopulmonary bypass were selected. Pre-, intra- and postoperative data from patients who were not successfully weaned after reintubation and who underwent an elective tracheotomy were compared. Parameters of respiratory mechanics such as respiratory complications, oxygenation, and cardiac, renal, and neurological function were evaluated. Weaning success was defined as the ability of a patient to tolerate 48 hours without pressure or flow support from a mechanical ventilator. A patient was considered to have failed weaning if they died or remained under ventilation for more than 8 weeks. Of the 52 patients studied, 25 were successfully weaned, 21 died, and 6 remained ventilated for more than 8 weeks. We found significant statistical differences (P < 0.05) between the groups with respect to success or failure in LVEF (P = 0.0035), the need for vasoactive agents (P = 0.0018), and renal failure (P = 0.002). Parameters of respiratory mechanics and oxygenation (eg, static airway compliance, airway resistance) did not influence the success or failure of weaning. There was a significant difference in relation to the presence of pneumonia (P = 0.0086) between the two groups. Although neurological complications were more frequent in patients in the weaning success group, the failure group had lower GCS scores, which is indicative of worse prognoses. It is concluded that cardiac dysfunction, the need for dialysis, and pneumonia are determinants for weaning failure in patients undergoing long-term mechanical ventilation after cardiac surgery.